Impact of Exercise and Metabolic Disorders on Heat Shock Proteins and Vascular Inflammation

Noble, Earl G.; Shen, Garry X.

doi:https://doi.org/10.1155/2012/836519

Autoimmune Diseases

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Special Issue

Heat-shock Proteins in Autoimmunity

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Review Article | Open Access

Volume 2012 | Article ID 836519 | https://doi.org/10.1155/2012/836519

Impact of Exercise and Metabolic Disorders on Heat Shock Proteins and Vascular Inflammation

Earl G. Noble¹and Garry X. Shen²

Academic Editor: Boel de Paepe

Received30 Jun 2012

Revised20 Sept 2012

Accepted06 Nov 2012

Published17 Dec 2012

Abstract

Heat shock proteins (Hsp) play critical roles in the body’s self-defense under a variety of stresses, including heat shock, oxidative stress, radiation, and wounds, through the regulation of folding and functions of relevant cellular proteins. Exercise increases the levels of Hsp through elevated temperature, hormones, calcium fluxes, reactive oxygen species (ROS), or mechanical deformation of tissues. Isotonic contractions and endurance- type activities tend to increase Hsp60 and Hsp70. Eccentric muscle contractions lead to phosphorylation and translocation of Hsp25/27. Exercise-induced transient increases of Hsp inhibit the generation of inflammatory mediators and vascular inflammation. Metabolic disorders (hyperglycemia and dyslipidemia) are associated with type 1 diabetes (an autoimmune disease), type 2 diabetes (the common type of diabetes usually associated with obesity), and atherosclerotic cardiovascular disease. Metabolic disorders activate HSF/Hsp pathway, which was associated with oxidative stress, increased generation of inflammatory mediators, vascular inflammation, and cell injury. Knock down of heat shock factor-1 (HSF1) reduced the activation of key inflammatory mediators in vascular cells. Accumulating lines of evidence suggest that the activation of HSF/Hsp induced by exercise or metabolic disorders may play a dual role in inflammation. The benefits of exercise on inflammation and metabolism depend on the type, intensity, and duration of physical activity.

1. Introduction

The stress response is a self-protective mechanism against environmental stresses which is mediated via a group of evolutionally conserved proteins, heat shock proteins (Hsp). Hsp regulate the conformation and functions of a large number of cellular proteins in order to protect the body from stress [1]. The expression of Hsp is mainly modulated by a common transcription factor, heat shock factor-1 (HSF1). The activity, translocation, and expression of HSF1 respond to environmental stresses, such as heat shock, wounds, oxidative stress, and radiation [2]. Exercise is associated with transient elevations of Hsp expression, body temperature, hormones, and oxidative stress, which may reduce inflammatory mediators [3]. Metabolic disorders in common chronic diseases (diabetes, metabolic syndrome, and atherosclerotic cardiovascular disease) are associated with a prolonged stress response as a consequence of oxidative stress, altered hormone levels, vascular inflammation, and cell injury [4]. Type 1 diabetes is a common autoimmune disease characterized by pancreatic -cell destruction and insulin deficiency which can lead to poor circulation and vascular disease [5]. This paper summarized up-to-date knowledge on the relationship between stress responses, oxidative stress, and vascular inflammation under exercise or metabolic disorders. Selected literature searched using PubMed over a period from 1981 to 2012 is provided.

2. Heat Shock Proteins

Hsp has evolved to perform multiple roles within cells, organs, and organisms [1]. These ubiquitous proteins, which are found both inside and outside the cell [7], have a generalized function of interacting with other proteins, hence their designation as molecular chaperones [8]. These interactions may influence the structure of the client protein(s) so that it may be maintained in a conformation appropriate for functional folding, targeted for degradation, or altered as part of a signaling pathway. Most Hsp have a multitude of activities based upon their cellular location (including extracellular), the client proteins they interact with [9], and their phosphorylation status which may modulate their aggregation [10], their localization [11], or their activation of enzymatic pathways [12]. As a consequence, Hsp not only protect cells and organisms against proteotoxic stresses, but these proteins are also critical in normal functioning of several cellular processes [13]. Amongst those signaling pathways which involve Hsp are several which are implicated in regulation of immune and inflammatory systems [14, 15]. Although there is some controversy regarding their exact role [16], Hsp may activate the immune response [17] but also dampen the inflammatory pathways [14].

Hsp have normally been classified according to their molecular mass with small Hsp, such as αA- and αB-crystallin, Hsp20, 22, 25/27, and other Hsp60, the Hsp70 and 90 families and Hsp110, and their cochaperones (Table 1), often working in concert to maintain cell structure and function [6]. A new nomenclature has more recently been introduced for Hsp [18]; however, for the purposes of this paper, we will refer to the more common mass-based nomenclature (see Table 1).

3. Regulation of the Transcription of Hsp

The regulation of the transcription of Hsp is mainly through heat shock factors (HSF). HSF represents a family of transcription factors induced by both stressful and nonstressful stimuli. The fundamental structure of HSF has been well conserved from yeast to humans [2, 19]. Four isoforms of HSF have been reported. HSF1, 2, and 4 are present in humans. HSF1 is ubiquitously expressed in mammalian tissues and relatively abundant in heart, ovary, brain, and placenta [20]. HSF2 is expressed in very low levels in postnatal tissue [21], and HSF4 is mainly expressed in brain and lung [22]. Under basal conditions, HSF1 exists as a monomer. Under stress, HSF1 is converted to a trimer which is required for the binding to the responsive element (heat shock element) of HSF1 in the Hsp promoter. Phosphorylation of specific HSF1 residues is also required for activation [23, 24], and the multiple pathways potentially involved in these phosphorylations [25–28] probably provide tissue and stress specificity. A variety of stresses beside heat shock may activate or upregulate HSF1 [19, 29, 30]. Indeed, activation of HSF1 was detected in diet-induced atherosclerotic lesions in rabbits and humans [31, 32].

Given the importance of the heat shock response, it is not surprising that there are multiple redundant pathways by which the response may be activated [33]. Following exercise, it is likely that these pathways converge with the HSF1 through the translocation of the transcription factor from cytoplasm to nucleus [34, 35]. With exercise, likely candidates are the adrenergic stimuli associated with exercise operating through - and -adrenergic receptors [36–38] as well as elevated temperature and its attendant changes [39, 40] (see Figure 1).

Figure 1

Schematic representation of activation of HSF1 with exercise and accompanying increases in vascular stress. Exercise initiates a number of factors, including elevations in temperature, reactive oxygen species (ROS), intracellular calcium (Ca²⁺), and decreased energy status [1], which may result in intracellular protein modification leading to dissociation of the heat shock transcription factor (HSF1) and heat shock proteins Hsp in the cytoplasm [2]. In addition, exercise activates adrenergic and shear stress intracellular signaling pathways [3]. Consequently HSF1 trimerizes and binds to heat shock elements (HSE) of nuclear DNA [4], whereupon specific phosphorylation/dephosphorylation events lead to a heat shock response [5]. Adapted from Noble, Melling, and Milne [6].

4. Exercise and Hsp

Locke et al. [3] were the first to demonstrate that vigorous physical activity is associated with the induction of Hsp70 in rodents. Subsequently, increased expression of Hsp in humans following exercise was confirmed [41, 42]. As noted above, exercise is associated with many stressors, including elevated temperature, metabolic disturbances, altered calcium fluxes, increased production of reactive oxygen species (ROS), changed hormonal environment, and mechanical activation or deformation of tissues [13]. Exercise has also been described as inducing a mild inflammatory state [43]. The magnitude of the exercise stress, including whether it is acute or chronic, plays a major role in inducing the stress response. Generally, the more vigorous the exercise was, the greater the response was [40, 44–46]. Further, isotonic nondamaging contractions, such as these associated with endurance type activities, tend to lead to increases in Hsp60 and 70 with more limited responses in the small Hsp [3, 47]. In contrast, eccentric (often damaging) muscle contractions, also lead to increases, phosphorylation, and translocation of Hsp 25/27 and αB-crystallin [10, 48, 49]. These exercise-induced changes may be associated with protection of the mitochondria [50, 51], the sarcoplasmic reticulum [52], cytoskeletal protection [49], maintenance of enzymatic activity [53], and insulin sensitivity and glucose transport [54, 55]. With repetitive exercise (exercise training), an exercise-induced increase of Hsp70 is maintained whereas the initial response of other Hsp to exercise is diminished as training progresses [39].

Exercise involves the activation of specific muscles for movement but also requires the support of the neural, cardiovascular, and respiratory systems. The primary focus of investigators to date has been on skeletal and cardiac muscles. Such studies have suggested that in the sedentary state Hsp are expressed in a tissue-specific fashion [56]. Exercise is associated with changes in Hsp expression which are also specific to the Hsp in question [47, 49]. For example, Hsp70 almost always increases with exercise, whereas the cognate Hsc70 is not normally altered [57–60]. In a similar fashion, some tissues, such as myocardium, may demonstrate a more general response whereas skeletal muscle responds with fiber-specific changes [61, 62]. It is likely that differences in temperature reached during exercise [40] and the specific patters of muscle fiber activation [45] are responsible for some of these tissue-specific observations.

5. Exercise and Vascular Inflammation

Physical activity, or exercise, is known to improve overall health and protect against, delay the progress of, or ameliorate many common chronic diseases [63, 64], in particular those associated with whole body inflammation, including cardiovascular disease [65]. Although those individuals with the greatest cardiorespiratory fitness appear to benefit most [66], simply engaging in regular physical activity seems to be protective [67]. One of the primary targets that may benefit from increased physical activity is the vasculature [68–71]. Amongst the benefits of exercise on the vasculature are increased vasodilation and improved vascular compliance [72] which are likely a result of shear stress and cell stretch on both the endothelium and underlying smooth muscle [73, 74]. Exercise may protect the vasculature through a number of mechanisms [63, 68, 75] including reduced inflammation [76–79]. Short-term exercise reduces the levels of TNF-α, IL-6, plasminogen activator inhibitor-1 (PAI-1) [80], and cell adhesion molecules [81], protects against media-intimal hyperplasia [82, 83] and smooth muscle cell hypertrophy [83], and strengthens the endothelial barrier [84]. The anti-inflammatory role of exercise [43, 65, 78] is complicated; however, as intense unaccustomed exercise may be associated with increased cortisol [85], C-reactive protein [86], and modest increases in other proinflammatory cytokines [87].

Interestingly, heat shock exhibits beneficial effects on the vasculature which are similar to exercise, with reduced inflammation [88], reduced endothelial interaction with leukocytes [89], enhanced smooth muscle cell survival [90], and inhibition of myointimal hyperplasia and smooth muscle cell hypertrophy [91–95]. Although both heat shock and exercise are complex stressors likely leading to many changes in the integrated physiology of an organism, they both have some common characteristics including activation of stress hormones, ROS, and elevated temperatures leading to the activation of the heat shock response in a variety of tissues including the vasculature. Exercise increases ROS production, and ROS may play a signaling role to initiate the stress response [96]. Also, there is evidence that elevated temperature is critical for the activation of the heat shock response in exercising mammals [39, 40, 97, 98]. These similarities suggest that the protection conferred by exercise against myocardial ischemia-reperfusion injury [99] could be partially a consequence of the vascular expression of Hsp [100, 101]. Indeed, exercise leads to a rapid transcription of Hsp70 mRNA in the vasculature of rodents [62] which eventually results in protein accumulation [102, 103].

6. Vascular Function of Hsp

As throughout the rest of the body, Hsp likely play specific roles within the vasculature. The response of the vasculature to shear stress is complicated. Laminar flow, such as that associated with exercise, induces positive vascular remodeling, whereas turbulent or low flow, such as that associated with vascular inflammation and atherosclerosis, leads to adhesion of blood borne molecules and inflammation [104] (see Figure 2). The increased laminar flow associated with exercise causes endothelial cell remodeling which includes the activation of a number of signaling pathways and either activation or enhanced expression of Hsp [73, 105–107]. Hsp25/27, which is phosphorylated in association with shear stress [105], is involved in cytoskeletal organization [108]. Hsp20 is associated with αB-crystallin in cardiac tissue [109], and both are involved in flow-mediated smooth muscle relaxation [110–112]. Indeed, Hsp25/27 and Hsp20/αB-crystallin may reciprocally assist in controlling venous tone [113]. Hsp70 may modulate vascular contractility through thick filament regulation [114], and Hsp90 is intricately involved in activation of endothelial nitric oxide synthase (eNOS) and the subsequent release of nitric oxide (NO) and vascular relaxation [115].

(a)

(b)

(c)

Figure 2

Scheme for relationships between exercise-associated hemodynamic changes, inflammatory response, and Hsp. (a) Low or turbulent flow is associated with leukocyte extravasation [1] and expression of adhesion molecules [2], resulting in intimal hyperplasia, cell apoptosis [3] and inflammatory signaling [4]. The associated inflammatory signaling leads to increased oxidative stress, induction of inflammatory pathways such as c-Jun NH₂-terminal kinase (JNK) [5] and NF-κB [6], and suppression of endothelial nitric oxide (eNOS) and oxidation of nitric oxide (NO) [7]. (b) In contrast, an exercise induced increase in laminar shear stress activates eNOS [1] and HSF1 [2]. HSF1 activation leads to increased heat shock proteins 25, 70, and 90 (Hsp25, Hsp70, and Hsp90) [3] which may inhibit many of these inflammatory processes indirectly via activation of eNOS signaling (Hsp90) [4] and directly through suppression of oxidative stress (Hsps 25, 70, and 90) [5] and inflammatory signaling including via the NF-κB pathway (Hsps 25 and 70) [6]. (c) Hsp may also directly reduce apoptosis (Hsps 70 and 90) [1] and hyperplasia (Hsp 70) [2]. Hsp70 has further been implicated in decreased expression of adhesion molecules [3] leading to a reduction of leukocyte extravasation [4] and expression of inflammatory cytokines [6]. Hsp70 also suppresses JNK signaling [5] further inhibiting inflammatory signaling and cytokine release. See text for a more complete description. — represents activating role; |— represents inhibitory role; - - - -: Hsp90 effects; ——: Hsp70 effects; -·-·-·-·: Hsp25 effects.

7. Activation of the Vasculature

Normal endothelium provides an effective barrier to foreign materials and does not interact with circulating factors. With a variety of chronic diseases, including atherosclerosis, metabolic syndrome, and diabetes, there is a subtle change in the endothelium which leads to their “activation” (see Figure 2(a)). Initially, increased membrane permeability leads to the accumulation and modification of proteins, lipids, and lipoproteins on endothelium [116]. The endothelium then becomes “sticky,” exhibiting proinflammatory markers such as monocyte chemotactic protein-1 (MCP-1), vascular and intracellular cell adhesion molecules (VCAM-1 and ICAM-1, resp.,) and greater nitrotyrosine content [117, 118]. This leads to the recruitment of blood borne cells which infiltrate the intima resulting in macrophages evolving to foam cells leading to further inflammation and release of pro-coagulant factors, smooth muscle cell death and migration, and the eventual formation of an atherosclerotic plaque [116, 119]. During the course of this progressive dysfunction, NO availability plays a key role, as it is responsible for limiting many of the above processes. However, elevated oxidative stress associated with vascular inflammation leads to diminished NO availability [120]. Oxidation of the eNOS cofactor, tetrahydrobiopterin, uncouples eNOS such that superoxide rather than NO is formed [121]. This leads to NO scavenging to peroxynitrites and ultimately reduced activation of eNOS and an overall reduction in eNOS content [120, 122].

Although there are a variety of pathways by which inflammation can influence this vascular dysfunction, the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) pathway plays a critical role in this process [123–125] (see Figure 2(a)). NF-κB has both anti- and proinflammatory roles; however, with progression of vascular damage, it primarily activates inflammatory pathways [123, 124, 126]. Members of the NF-κB family, including p50, p52, p65, relB, and C-Rel, form homo- or heterodimers which are found in the cytoplasm in an inactive state bound to the inhibitor IκB. Various stressors can release the IκB from NF-κB through a pathway which involves phosphorylation of IκB by the IKK complex (IKKα, IKKβ, and IKKγ). The phosphorylation of IκB leads to its degradation by the ubiquitin proteasome pathway. The degradation of IκB allows translocation of the NF-κB dimer to the nucleus, where depending on the NF-κB composition, recruited cofactors, and the sequence of targeted genes, variable responses may be observed [124, 127]. NF-κB may also be activated via an IKKα-specific, noncanonical pathway [127]. Knockdown of HSF1 reduced Hsp27 expression and increased angiotensin II-induced NF-κB activation in vascular smooth muscle cells [88]. This suggests that HSF1/Hsp 27 may mediate stress-activated vascular inflammation.

8. Anti-Inflammatory Actions of Hsp

It should be noted that Hsp, particularly extracellular Hsp, may play a key role in activating and exacerbating inflammation including vascular inflammation [17, 128–131] (see the following); however, given the anti-inflammatory phenotype associated with exercise and heat shock, it is likely that the predominate role in the progression of vascular disease is protective under these circumstances.

Both heat shock and exercise increase the vascular content or alter the phosphorylation status of various Hsp and both of these conditions are associated with anti-inflammatory states [14, 132]. Although exact mechanistic activities are often difficult to identify, activation of HSF1, which is the primary transcription factor involved in Hsp induction, may directly reduce general inflammation in vascular tissue [133], but most effects are probably through HSF1-induced increases in expression of Hsp [134] (see Figure 2(b)).

Hsp25/27 and Hsp70 can directly stimulate anti-inflammatory cytokines [135, 136], while Hsp70 can inhibit release of a variety of inflammatory cytokines including TNFα, HMGB1, and IL6 and IL1β [137–139]. This Hsp modulation of cytokine profile also reduces the presence of cell adhesion molecules and thereby leucocyte infiltration of the vascular wall [140, 141]. Hsp may reduce oxidative stress by a variety of mechanisms including facilitation of antioxidant pathways [10, 142, 143]. Of course the reduction in oxidative stress helps maintain NO bioavailability and reduces peroxynitrite formation [120]. In addition, increased Hsp90 in the vasculature has a direct positive effect on eNOS activation [115, 144–146], thereby maintaining vascular function (see Figures 2(b) and 2(c)).

9. Regulatory Role of Hsp on Apoptosis

As the inflammatory process progresses, a progressive cycle of intima expansion occurs with the death, proliferation, and migration of smooth muscle cells [147]. Accumulating lines of evidence suggest that Hsp intervene at multiple locations to inhibit cell death pathways including inhibition of death receptor signaling. Hsp25/27, 70, and 90 are involved in suppression of the mitochondria-dependent apoptosis, by directly limiting cytochrome c release [148, 149] and activation of various caspases [150, 151], by inhibiting caspase-independent pathways [152], and by inhibition of stress [153] and cell death receptor pathways [154, 155]. Hsp directly impacts on this pathway in several ways (Figures 2(b) and 2(c)). Hsp70 and Hsp25/27 can directly interact with IKKα, stabilizing it and preventing the inflammatory activation of the NF-κB pathway [156–158]. These effects appear to be dose and time dependent [159]. Secondly, the stabilization of the cytoskeleton and antiproliferative effects of Hsp25/27 processes negatively influenced by LDL [11] may inhibit inflammation-induced vascular damage [160]. Lastly, although the effects of Hsp on vascular health have been separated by the individual Hsp involved, there is evidence that effective vascular protection requires interaction of multiple types of Hsp [161].

10. Metabolic Disorders and the Stress Response

Metabolic disorders, including hyperglycemia, hypercholesterolemia, hypertriglyceridemia, modified low density lipoproteins (LDL), and insulin resistance, are often associated with diabetes, metabolic syndrome, vascular inflammation, and atherosclerotic cardiovascular disease. Hyperglycemia interrupts the colocalization of Hsp90 and eNOS in endothelial cells, which may affect the production of NO and endothelium-dependent vascular relaxation [162]. Circulating levels of Hsp60 are correlated with triglycerides and small dense LDL in patients with untreated periodontitis [4]. Restriction stress increases the production of Hsp70, MCP-1, PAI-1, and monocyte adhesion but decreases adiponectin in mice [163]. The levels of Hsp27 antigen and antibody in serum of diabetic patients are associated with cardiovascular complications and insulin resistance [164]. Oxidized LDL (oxLDL) has been considered as a circulating marker for coronary artery disease [165]. Glycation increases lipid peroxidation of LDL [166]. The levels of glycated LDL (glyLDL) and oxLDL are increased in diabetic patients [167]. GlyLDL treatment increases the abundance of HSF1 and Hsp70 in endothelial cells [128]. GlyLDL or oxLDL increases the binding of HSF1 to the PAI-1 promoter and PAI-1 expression in endothelial cells [128, 168]. PAI-1 is not only a physiological inhibitor of tissue and urokinase plasminogen activator but also a marker for inflammation. Reduced fibrinolytic activity is associated with coronary artery disease and diabetic vascular complications [169]. Elevated levels of PAI-1 were detected in acute and chronic inflammatory conditions [170, 171]. Increased levels of circulatory PAI-1 have been considered as a marker of inflammation. However, the precise role of PAI-1 in inflammation remains to be determined. Antioxidants inhibit oxLDL or glyLDL-induced increases of HSF1, PAI-1, and ROS in endothelial cells, which suggests that oxidative stress may play a regulatory role in metabolic stress-induced activation of the stress response and vascular inflammation [168]. In certain stress conditions, such as massive bleeding and wounds, HSF1-mediated PAI-1 production may be protective for the body through its prothrombotic and antifibrinolytic effects. However, chronic elevation of PAI-1 production induced by metabolic disorders may lead to thrombotic tendency and ischemic events. GlyLDL or oxLDL impairs activities of mitochondrial respiratory chain enzymes in vascular endothelial cells [172, 173]. OxLDL induced oxidative stress, activation of HSF1 [168], and apoptosis and the imbalance between caspase-3 and Bcl-2 in endothelial cells [174]. The role of HSF1/Hsp in metabolic disorders-induced vascular inflammation and injury remains to be further investigated but as noted above appears to be both pro- and anti-inflammatory.

11. Inflammatory Imbalance in Type 1 Diabetes and Effects of Exercise

The major underlying mechanism for insulin deficiency in type 1 diabetes is -cell destruction induced by an autoimmune response. Imbalance between autoreactive Th1 lymphocytes and protective Th2 lymphocytes is found in type 1 diabetes, which leads to both proinflammatory cytokines (IL-2, IL-12, TNF-, and IFN-) and anti-inflammatory cytokines (IL-4, IL-6, IL-10, and IL-13) [175]. Interactions between proinflammatory cytokines (TNF- and IFN-) and the receptors on membrane of -cells may activate the caspase cascade and result in apoptosis. TNF- and IFN- may also activate macrophages, which leads to the release of TNF-, IL-1, NO, and superoxide, which may increase oxidative stress and downregulation of Bcl-2, which activate NF-κB and -cell apoptosis leading to insulin deficiency [176]. Active macrophages may increase iNOS activity. Elevated NO generation in -cells may cause oxidative stress, insulin resistance, and -cell damage [177]. Oxidative stress may reduce insulin secretion from -cells through stimulating the expression of uncoupling protein 2 (UCP2). UCP2 may inhibit electron transport in mitochondria and increase ROS production. Prolonged hyperglycemia may increase UCP2 in -cells, which may contribute to insulin deficiency in both type 1 and type 2 diabetes [178]. Relatively less literature is available on the impact of exercise on the clinical outcome or inflammatory mediators in type 1 diabetic animals or humans. A recent study demonstrated resistance exercise before aerobic exercise improved glycemic stability throughout exercise and reduced postexercise hypoglycemia in type 1 diabetic patients [179]. Exercise induced less increase of Hsp70 in insulin-deficient diabetic rats than in control rats [180]. The impact of exercise on inflammatory mediators and the relationship with glucose metabolism in type 1 diabetes remain to be more fully investigated.

12. Conclusion

Both exercise and metabolic stress activate HSF1/Hsp pathway in the body. Transient stress responses induced by regular and moderate exercise tend to downregulate vascular inflammation and protect vessels from injury. Chronic stress responses induced by metabolic disorders upregulate inflammatory mediators, which leads to vascular inflammation, apoptosis, and injury. The HSF1/Hsp-mediated stress response to exercise and metabolic disorders play, distinguishable and possibly opposite roles in vascular inflammation, which may be related to the involvement of different types of Hsp, body temperature, or shear stress of blood flow. The consequences of stress responses induced by exercise and metabolic disorders, particularly of autoimmune diseases such as type 1 diabetes, on vascular inflammation require further investigation.

Acknowledgments

The authors thank for Ms. Laura Dolor typing and the grant support from Canadian Institutes of Health Research, Canadian Diabetes Association, and Manitoba Health Research Council to relevant projects funded to E. Noble and G. X. Shen.

References

M. E. Feder and G. E. Hofmann, “Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology,” Annual Review of Physiology, vol. 61, pp. 243–282, 1999.
View at: Publisher Site | Google Scholar
K. A. Morano and D. J. Thiele, “Heat shock factor function and regulation in response to cellular stress, growth, and differentiation signals,” Gene Expression, vol. 7, no. 4–6, pp. 271–282, 1999.
View at: Google Scholar
M. Locke, E. G. Noble, and B. G. Atkinson, “Exercising mammals synthesize stress proteins,” American Journal of Physiology, vol. 258, no. 4, pp. C723–C729, 1990.
View at: Google Scholar
M. Rizzo, F. Cappello, R. Marfil et al., “Heat-shock protein 60 kDa and atherogenic dyslipidemia in patients with untreated mild periodontitis: a pilot study,” Cell Stress and Chaperones, vol. 17, pp. 399–407, 2012.
View at: Google Scholar
A. L. Notkins and A. Lernmark, “Autoimmune type 1 diabetes: resolved and unresolved issues,” Journal of Clinical Investigation, vol. 108, no. 9, pp. 1247–1252, 2001.
View at: Publisher Site | Google Scholar
E. G. Noble, C. W. J. Melling, and K. J. Milne, “HSP, exercise and skeletal muscle,” in Heat Shock Proteins and Whole Body Physiology, A. A. A. Asea and B. K. Pedersen, Eds., Heat Shock Proteins, pp. 285–316, Springer Science+Business Media, Dordrecht, The Netherlands, 2010.
View at: Google Scholar
P. L. Moseley, “Heat shock proteins and the inflammatory response,” Annals of the New York Academy of Sciences, vol. 856, pp. 206–213, 1998.
View at: Google Scholar
J. Ellis, “Proteins as molecular chaperones,” Nature, vol. 328, no. 6129, pp. 378–379, 1987.
View at: Google Scholar
J. Fontana, D. Fulton, Y. Chen et al., “Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release,” Circulation Research, vol. 90, no. 8, pp. 866–873, 2002.
View at: Publisher Site | Google Scholar
A. P. Arrigo, “The cellular “networking” of mammalian Hsp27 and its functions in the control of protein folding, redox state and apoptosis,” Advances in Experimental Medicine and Biology, vol. 594, pp. 14–26, 2007.
View at: Publisher Site | Google Scholar
M. García-Arguinzonis, T. Padró, R. Lugano, V. Llorente-Cortes, and L. Badimon, “Low-density lipoproteins induce heat shock protein 27 dephosphorylation, oligomerization, and subcellular relocalization in human vascular smooth muscle cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 6, pp. 1212–1219, 2010.
View at: Publisher Site | Google Scholar
A. Lakshmikuttyamma, P. Selvakumar, and R. K. Sharma, “Interaction between heat shock protein 70 kDa and calcineurin in cardiovascular systems (review),” International Journal of Molecular Medicine, vol. 17, no. 3, pp. 419–423, 2006.
View at: Google Scholar
E. G. Noble, K. J. Milne, and C. W. J. Melling, “Heat shock proteins and exercise: a primer,” Applied Physiology, Nutrition and Metabolism, vol. 33, no. 5, pp. 1050–1075, 2008.
View at: Google Scholar
Q. Jones, T. S. Voegeli, G. Li, Y. Chen, and R. W. Currie, “Heat shock proteins protect against ischemia and inflammation through multiple mechanisms,” Inflammation and Allergy, vol. 10, no. 4, pp. 247–259, 2011.
View at: Google Scholar
A. M. Shields, G. S. Panayi, and V. M. Corrigall, “A new-age for biologic therapies: long-term drug-free therapy with BiP?” Frontiers in Immunology, vol. 3, article 17, 2012.
View at: Google Scholar
W. van Eden, R. Spiering, F. Broere, and Z. R. van der Zee, “A case of mistaken identity: HSPs are no DAMPs but DAMPERs,” Cell Stress and Chaperones, vol. 17, no. 3, pp. 281–292, 2012.
View at: Google Scholar
J. Radons and G. Multhoff, “Immunostimulatory functions of membrane-bound and exported heat shock protein 70,” Exercise Immunology Review, vol. 11, pp. 17–33, 2005.
View at: Google Scholar
H. H. Kampinga, J. Hageman, M. J. Vos et al., “Guidelines for the nomenclature of the human heat shock proteins,” Cell Stress and Chaperones, vol. 14, no. 1, pp. 105–111, 2009.
View at: Publisher Site | Google Scholar
E. Christians, A. A. Davis, S. D. Thomas, and I. J. Benjamin, “Maternal effect of Hsf1 on reproductive success,” Nature, vol. 407, no. 6805, pp. 693–694, 2000.
View at: Publisher Site | Google Scholar
K. D. Sarge, V. Zimarino, K. Holm, C. Wu, and R. I. Morimoto, “Cloning and characterization of two mouse heat shock factors with distinct inducible and constitutive DNA-binding ability,” Genes and Development, vol. 5, no. 10, pp. 1902–1911, 1991.
View at: Google Scholar
M. Rallu, M. T. Loones, Y. Lallemand, R. Morimoto, M. Morange, and V. Mezger, “Function and regulation of heat shock factor 2 during mouse embryogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 6, pp. 2392–2397, 1997.
View at: Publisher Site | Google Scholar
M. Tanabe, N. Sasai, K. Nagata et al., “The mammalian HSF4 gene generates both an activator and a repressor of heat shock genes by alternative splicing,” Journal of Biological Chemistry, vol. 274, no. 39, pp. 27845–27856, 1999.
View at: Publisher Site | Google Scholar
N. F. Mivechi, A. C. Koong, A. J. Giaccia, and G. M. Hahn, “Analysis of HSF-1 phosphorylation in A549 cells treated with a variety of stresses,” International Journal of Hyperthermia, vol. 10, no. 3, pp. 371–379, 1994.
View at: Google Scholar
W. Xia and R. Voellmy, “Hyperphosphorylation of heat shock transcription factor 1 is correlated with transcriptional competence and slow dissociation of active factor trimers,” Journal of Biological Chemistry, vol. 272, no. 7, pp. 4094–4102, 1997.
View at: Publisher Site | Google Scholar
B. Chu, F. Soncin, B. D. Price, M. A. Stevenson, and S. K. Calderwood, “Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1,” Journal of Biological Chemistry, vol. 271, no. 48, pp. 30847–30857, 1996.
View at: Publisher Site | Google Scholar
J. Kim, A. Nueda, Y. H. Meng, W. S. Dynan, and N. F. Mivechi, “Analysis of the phosphorylation of human heat shock transcription factor-1 by MAP kinase family members,” Journal of Cellular Biochemistry, vol. 67, no. 1, pp. 43–54, 1997.
View at: Google Scholar
R. Dai, W. Frejtag, B. He, Y. Zhang, and N. F. Mivechi, “c-Jun NH2-terminal kinase targeting and phosphorylation of heat shock factor-1 suppress its transcriptional activity,” Journal of Biological Chemistry, vol. 275, no. 24, pp. 18210–18218, 2000.
View at: Publisher Site | Google Scholar
C. I. Holmberg, S. E. F. Tran, J. E. Eriksson, and L. Sistonen, “Multisite phosphorylation provides sophisticated regulation of transcription factors,” Trends in Biochemical Sciences, vol. 27, no. 12, pp. 619–627, 2002.
View at: Publisher Site | Google Scholar
K. A. Morano and D. J. Klionsky, “Differential effects of compartment deacidification on the targeting of membrane and soluble proteins to the vacuole in yeast,” Journal of Cell Science, vol. 107, pp. 2813–2824, 1994.
View at: Google Scholar
S. Airaksinen, T. Jokilehto, C. M. I. Råbergh, and M. Nikinmaa, “Heat- and cold-inducible regulation of HSP70 expression in zebrafish ZF4 cells,” Comparative Biochemistry and Physiology B, vol. 136, no. 2, pp. 275–282, 2003.
View at: Publisher Site | Google Scholar
B. Metzler, R. Abia, M. Ahmad et al., “Activation of heat shock transcription factor 1 in atherosclerosis,” American Journal of Pathology, vol. 162, no. 5, pp. 1669–1676, 2003.
View at: Google Scholar
P. A. Berberian, W. Myers, M. Tytell, V. Challa, and M. G. Bond, “Immunohistochemical localization of heat shock protein-70 in normal-appearing and atherosclerotic specimens of human arteries,” American Journal of Pathology, vol. 136, no. 1, pp. 71–80, 1990.
View at: Google Scholar
S. I. Nadeau and J. Landry, “Mechanisms of activation and regulation of the heat shock-sensitive signaling pathways,” Advances in Experimental Medicine and Biology, vol. 594, pp. 100–113, 2007.
View at: Publisher Site | Google Scholar
R. I. Morimoto, “Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators,” Genes and Development, vol. 12, no. 24, pp. 3788–3796, 1998.
View at: Google Scholar
C. W. Melling, D. B. Thorp, and E. G. Noble, “Regulation of myocardial heat shock protein 70 gene expression following exercise,” Journal of Molecular and Cellular Cardiology, vol. 37, no. 4, pp. 847–855, 2004.
View at: Publisher Site | Google Scholar
Z. Paroo and E. G. Noble, “Isoproterenol potentiates exercise-induction of Hsp70 in cardiac and skeletal muscle,” Cell Stress and Chaperones, vol. 4, no. 3, pp. 199–204, 1999.
View at: Publisher Site | Google Scholar
J. D. Johnson, J. Campisi, C. M. Sharkey, S. L. Kennedy, M. Nickerson, and M. Fleshner, “Adrenergic receptors mediate stress-induced elevations in extracellular Hsp72,” Journal of Applied Physiology, vol. 99, no. 5, pp. 1789–1795, 2005.
View at: Publisher Site | Google Scholar
C. W. J. Melling, D. B. Thorp, K. J. Milne, M. P. Krause, and E. G. Noble, “Exercise-mediated regulation of Hsp70 expression following aerobic exercise training,” American Journal of Physiology, vol. 293, no. 6, pp. H3692–H3698, 2007.
View at: Publisher Site | Google Scholar
M. B. Harris and J. W. Starnes, “Effects of body temperature during exercise training on myocardial adaptations,” American Journal of Physiology, vol. 280, no. 5, pp. H2271–H2280, 2001.
View at: Google Scholar
K. J. Milne, D. B. Thorp, M. Krause, and E. G. Noble, “Core temperature is a greater influence than endogenous 17beta-estradiol on the exercise-induced accumulation of myocardial heat shock protein mRNA,” Canadian Journal of Physiology and Pharmacology, vol. 89, no. 11, pp. 855–860, 2011.
View at: Google Scholar
F. Reichsman, S. P. Scordilis, P. M. Clarkson, and W. J. Evans, “Muscle protein changes following eccentric exercise in humans,” European Journal of Applied Physiology and Occupational Physiology, vol. 62, no. 4, pp. 245–250, 1991.
View at: Google Scholar
A. Puntschart, M. Vogt, H. R. Widmer, H. Hoppeler, and R. Billeter, “Hsp70 expression in human skeletal muscle after exercise,” Acta Physiologica Scandinavica, vol. 157, no. 4, pp. 411–417, 1996.
View at: Google Scholar
P. N. Shek and R. J. Shephard, “Physical exercise as a human model of limited inflammatory response,” Canadian Journal of Physiology and Pharmacology, vol. 76, no. 5, pp. 589–597, 1998.
View at: Google Scholar
H. A. Demirel, S. K. Powers, H. Naito, and N. Tumer, “The effects of exercise duration on adrenal HSP72/73 induction in rats,” Acta Physiologica Scandinavica, vol. 167, no. 3, pp. 227–231, 1999.
View at: Publisher Site | Google Scholar
K. J. Milne and E. G. Noble, “Exercise-induced elevation of HSP70 is intensity dependent,” Journal of Applied Physiology, vol. 93, no. 2, pp. 561–568, 2002.
View at: Google Scholar
E. Fehrenbach, A. M. Niess, K. Voelker, H. Northoff, and F. C. Mooren, “Exercise intensity and duration affect blood soluble HSP72,” International Journal of Sports Medicine, vol. 26, no. 7, pp. 552–557, 2005.
View at: Publisher Site | Google Scholar
J. P. Morton, D. P. M. MacLaren, N. T. Cable et al., “Time course and differential responses of the major heat shock protein families in human skeletal muscle following acute nondamaging treadmill exercise,” Journal of Applied Physiology, vol. 101, no. 1, pp. 176–182, 2006.
View at: Publisher Site | Google Scholar
T. J. Koh and J. Escobedo, “Cytoskeletal disruption and small heat shock protein translocation immediately after lengthening contractions,” American Journal of Physiology, vol. 286, no. 3, pp. C713–C722, 2004.
View at: Google Scholar
G. Paulsen, K. Vissing, J. M. Kalhovde et al., “Maximal eccentric exercise induces a rapid accumulation of small heat shock proteins on myofibrils and a delayed HSP70 response in humans,” American Journal of Physiology, vol. 293, no. 2, pp. R844–R853, 2007.
View at: Publisher Site | Google Scholar
L. Bornman, C. M. L. Steinmann, G. S. Gericke, and B. S. Polla, “In vivo heat shock protects rat myocardial mitochondria,” Biochemical and Biophysical Research Communications, vol. 246, no. 3, pp. 836–840, 1998.
View at: Publisher Site | Google Scholar
I. A. Sammut and J. C. Harrison, “Cardiac mitochondrial complex activity is enhanced by heat shock proteins,” Clinical and Experimental Pharmacology and Physiology, vol. 30, no. 1-2, pp. 110–115, 2003.
View at: Publisher Site | Google Scholar
A. R. Tupling, A. O. Gramolini, T. A. Duhamel et al., “HSP70 binds to the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA1a) and prevents thermal inactivation,” Journal of Biological Chemistry, vol. 279, no. 50, pp. 52382–52389, 2004.
View at: Publisher Site | Google Scholar
G. C. Melkani, A. Cammarato, and S. I. Bernstein, “αB-crystallin maintains skeletal muscle myosin enzymatic activity and prevents its aggregation under heat-shock stress,” Journal of Molecular Biology, vol. 358, no. 3, pp. 635–645, 2006.
View at: Publisher Site | Google Scholar
I. Kurucz, A. Morva, A. Vaag et al., “Decreased expression of heat shock protein 72 in skeletal muscle of patients with type 2 diabetes correlates with insulin resistance,” Diabetes, vol. 51, no. 4, pp. 1102–1109, 2002.
View at: Google Scholar
J. Chung, A. K. Nguyen, D. C. Henstridge et al., “HSP72 protects against obesity-induced insulin resistance,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 5, pp. 1739–1744, 2008.
View at: Publisher Site | Google Scholar
R. M. Tanguay, Y. Wu, and E. W. Khandjian, “Tissue-specific expression of heat shock proteins of the mouse in the absence of stress,” Developmental Genetics, vol. 14, no. 2, pp. 112–118, 1993.
View at: Google Scholar
D. A. Kelly, P. M. Tiidus, M. E. Houston, and E. G. Noble, “Effect of vitamin E deprivation and exercise training on induction of HSP70,” Journal of Applied Physiology, vol. 81, no. 6, pp. 2379–2385, 1996.
View at: Google Scholar
R. Hernando and R. Manso, “Muscle fibre stress in response to exercise. Synthesis, accumulation and isoform transitions of 70-kDa heat-shock proteins,” European Journal of Biochemistry, vol. 243, no. 1-2, pp. 460–467, 1997.
View at: Google Scholar
A. McArdle, D. Pattwell, A. Vasilaki, R. D. Griffiths, and M. J. Jackson, “Contractile activity-induced oxidative stress: cellular origin and adaptive responses,” American Journal of Physiology, vol. 280, no. 3, pp. C621–C627, 2001.
View at: Google Scholar
Z. Murlasits, R. G. Cutlip, K. B. Geronilla, K. M. K. Rao, W. F. Wonderlin, and S. E. Alway, “Resistance training increases heat shock protein levels in skeletal muscle of young and old rats,” Experimental Gerontology, vol. 41, no. 4, pp. 398–406, 2006.
View at: Publisher Site | Google Scholar
A. R. Tupling, E. Bombardier, R. D. Stewart, C. Vigna, and A. E. Aqui, “Muscle fiber type-specific response of Hsp70 expression in human quadriceps following acute isometric exercise,” Journal of Applied Physiology, vol. 103, no. 6, pp. 2105–2111, 2007.
View at: Publisher Site | Google Scholar
J. T. Silver, H. Kowalchuk, and E. G. Noble, “hsp70 mRNA temporal localization in rat skeletal myofibers and blood vessels post-exercise,” Cell Stress and Chaperones, vol. 17, no. 1, pp. 109–120, 2012.
View at: Google Scholar
D. E. R. Warburton, C. W. Nicol, and S. S. D. Bredin, “Health benefits of physical activity: the evidence,” Canadian Medical Association Journal, vol. 174, no. 6, pp. 801–809, 2006.
View at: Publisher Site | Google Scholar
U. M. Kujala, “Evidence on the effects of exercise therapy in the treatment of chronic disease,” British Journal of Sports Medicine, vol. 43, no. 8, pp. 550–555, 2009.
View at: Publisher Site | Google Scholar
B. K. Pedersen, “Exercise-induced myokines and their role in chronic diseases,” Brain, Behavior, and Immunity, vol. 25, no. 5, pp. 811–816, 2011.
View at: Publisher Site | Google Scholar
S. N. Blair, Y. Cheng, and J. S. Holder, “Is physical activity or physical fitness more important in defining health benefits?” Medicine and Science in Sports and Exercise, vol. 33, supplement 6, pp. S379–S399, 2001.
View at: Google Scholar
I. M. Lee and P. J. Skerrett, “Physical activity and all-cause mortality: what is the dose-response relation?” Medicine and Science in Sports and Exercise, vol. 33, supplement 6, pp. S459–S471, 2001.
View at: Google Scholar
F. P. Leung, L. M. Yung, I. Laher, X. Yao, Z. Y. Chen, and Y. Huang, “Exercise, vascular wall and cardiovascular diseases: an update (part 1),” Sports Medicine, vol. 38, no. 12, pp. 1009–1024, 2008.
View at: Google Scholar
M. Y. Lai, I. Laher, X. Yao, Y. C. Zhen, Y. Huang, and P. L. Fung, “Exercise, vascular wall and cardiovascular diseases: an update (part 2),” Sports Medicine, vol. 39, no. 1, pp. 45–63, 2009.
View at: Publisher Site | Google Scholar
D. J. Green, “Exercise training as vascular medicine: direct impacts on the vasculature in humans,” Exercise and Sport Sciences Reviews, vol. 37, no. 4, pp. 196–202, 2009.
View at: Publisher Site | Google Scholar
J. Padilla, G. H. Simmons, S. B. Bender, A. A. Arce-Esquivel, J. J. Whyte, and M. H. Laughlin, “Vascular effects of exercise: endothelial adaptations beyond active muscle beds,” Physiology, vol. 26, no. 3, pp. 132–145, 2011.
View at: Google Scholar
D. J. Green, A. Spence, J. R. Halliwill, N. T. Cable, and D. H. J. Thijssen, “Exercise and vascular adaptation in asymptomatic humans,” Experimental Physiology, vol. 96, no. 2, pp. 57–70, 2011.
View at: Publisher Site | Google Scholar
X. L. Wang, A. Fu, S. Raghavakaimal, and H. C. Lee, “Proteomic analysis of vascular endothelial cells in response to laminar shear stress,” Proteomics, vol. 7, no. 4, pp. 588–596, 2007.
View at: Publisher Site | Google Scholar
M. H. Laughlin, S. C. Newcomer, and S. B. Bender, “Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype,” Journal of Applied Physiology, vol. 104, no. 3, pp. 588–600, 2008.
View at: Publisher Site | Google Scholar
P. T. Katzmarzyk and S. A. Lear, “Physical activity for obese individuals: a systematic review of effects on chronic disease risk factors,” Obesity Reviews, vol. 13, no. 2, pp. 95–105, 2012.
View at: Google Scholar
E. S. Ford, “Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults,” Epidemiology, vol. 13, no. 5, pp. 561–568, 2002.
View at: Google Scholar
S. Mora, N. Cook, J. E. Buring, P. M. Ridker, and I. M. Lee, “Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms,” Circulation, vol. 116, no. 19, pp. 2110–2118, 2007.
View at: Publisher Site | Google Scholar
N. P. Walsh, M. Gleeson, D. B. Pyne et al., “Position statement. Part two: maintaining immune health,” Exercise Immunology Review, vol. 17, pp. 6–63, 2011.
View at: Google Scholar
M. Gleeson, N. C. Bishop, D. J. Stensel, M. R. Lindley, S. S. Mastana, and M. A. Nimmo, “The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease,” Nature Reviews Immunology, vol. 11, no. 9, pp. 607–615, 2011.
View at: Publisher Site | Google Scholar
A. Izadpanah, R. J. Barnard, A. J. Almeda et al., “A short-term diet and exercise intervention ameliorates inflammation and markers of metabolic health in overweight/obese children,” American Journal of Physiology, vol. 303, no. 4, pp. E542–E550, 2012.
View at: Google Scholar
T. Saetre, E. Enoksen, T. Lyberg et al., “Supervised exercise training reduces plasma levels of the endothelial inflammatory markers E-selectin and ICAM-1 in patients with peripheral arterial disease,” Angiology, vol. 62, no. 4, pp. 301–305, 2011.
View at: Publisher Site | Google Scholar
K. L. Moreau, A. E. Silver, F. A. Dinenno, and D. R. Seals, “Habitual aerobic exercise is associated with smaller femoral artery intima-media thickness with age in healthy men and women,” European Journal of Cardiovascular Prevention and Rehabilitation, vol. 13, no. 5, pp. 805–811, 2006.
View at: Publisher Site | Google Scholar
K. Pahkala, O. J. Heinonen, O. Simell et al., “Association of physical activity with vascular endothelial function and intima-media thickness,” Circulation, vol. 124, no. 18, pp. 1956–1963, 2011.
View at: Google Scholar
Y. H. Ding, Y. Ding, J. Li, D. A. Bessert, and J. A. Rafols, “Exercise pre-conditioning strengthens brain microvascular integrity in a rat stroke model,” Neurological Research, vol. 28, no. 2, pp. 184–189, 2006.
View at: Publisher Site | Google Scholar
M. D. Van Bruggen, A. C. Hackney, R. G. McMurray, and K. S. Ondrak, “The relationship between serum and salivary cortisol levels in response to different intensities of exercise,” International Journal of Sports Physiology and Performance, vol. 6, no. 3, pp. 396–407, 2011.
View at: Google Scholar
A. E. Mendham, C. E. Donges, E. A. Liberts, and R. Duffield, “Effects of mode and intensity on the acute exercise-induced IL-6 and CRP responses in a sedentary, overweight population,” European Journal of Applied Physiology, vol. 111, no. 6, pp. 1035–1045, 2011.
View at: Publisher Site | Google Scholar
J. P. R. Scott, C. Sale, J. P. Greeves, A. Casey, J. Dutton, and W. D. Fraser, “Effect of exercise intensity in the cytokine response to an acute bout of running,” Medicine & Science in Sports & Exercise, vol. 43, no. 12, pp. 2297–2306, 2011.
View at: Publisher Site | Google Scholar
Y. Chen and R. W. Currie, “Small interfering RNA knocks down heat shock factor-1 (HSF-1) and exacerbates pro-inflammatory activation of NF-κB and AP-1 in vascular smooth muscle cells,” Cardiovascular Research, vol. 69, no. 1, pp. 66–75, 2006.
View at: Publisher Site | Google Scholar
P. H. McCormick, G. Chen, S. Tierney, C. J. Kelly, and D. J. Bouchier-Hayes, “Clinically applicable thermal preconditioning attenuates leukocyte-endothelial interactions,” Journal of the American College of Surgeons, vol. 197, no. 1, pp. 71–78, 2003.
View at: Publisher Site | Google Scholar
A. D. Johnson, P. A. Berberian, M. Tytell, and M. G. Bond, “Differential distribution of 70-kD heat shock proteins in atherosclerosis. Its potential role in arterial SMC survival,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 15, no. 1, pp. 27–36, 1995.
View at: Google Scholar
D. G. Neschis, S. D. Safford, P. N. Raghunath et al., “Thermal preconditioning before rat arterial balloon injury: limitation of injury and sustained reduction of intimal thickening,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 18, no. 1, pp. 120–126, 1998.
View at: Google Scholar
E. M. Connolly, C. J. Kelly, G. Chen et al., “Pharmacological induction of HSP27 attenuates intimal hyperplasia in vivo,” European Journal of Vascular and Endovascular Surgery, vol. 25, no. 1, pp. 40–47, 2003.
View at: Publisher Site | Google Scholar
D. J. Tessier, P. Komalavilas, B. Liu et al., “Transduction of peptide analogs of the small heat shock-related protein HSP20 inhibits intimal hyperplasia,” Journal of Vascular Surgery, vol. 40, no. 1, pp. 106–114, 2004.
View at: Publisher Site | Google Scholar
Y. Zheng, C. N. Im, and J. S. Seo, “Inhibitory effect of Hsp70 on angiotensin II-induced vascular smooth muscle cell hypertrophy,” Experimental and Molecular Medicine, vol. 38, no. 5, pp. 509–518, 2006.
View at: Google Scholar
L. Denes, Z. Bori, E. Csonka, L. Entz, and Z. Nagy, “Reverse regulation of endothelial cells and myointimal hyperplasia on cell proliferation by a heatshock protein-coinducer after hypoxia,” Stroke, vol. 39, no. 3, pp. 1022–1024, 2008.
View at: Publisher Site | Google Scholar
E. Fehrenbach and H. Northoff, “Free radicals, exercise, apoptosis, and heat shock proteins,” Exercise Immunology Review, vol. 7, pp. 66–89, 2001.
View at: Google Scholar
J. L. Staib, J. C. Quindry, J. P. French, D. S. Criswell, and S. K. Powers, “Increased temperature, not cardiac load, activates heat shock transcription factor 1 and heat shock protein 72 expression in the heart,” American Journal of Physiology, vol. 292, no. 1, pp. R432–R439, 2007.
View at: Publisher Site | Google Scholar
Y. Ogura, H. Naito, S. Akin et al., “Elevation of body temperature is an essential factor for exercise-increased extracellular heat shock protein 72 level in rat plasma,” American Journal of Physiology, vol. 294, no. 5, pp. R1600–R1607, 2008.
View at: Publisher Site | Google Scholar
Z. Paroo, J. V. Haist, M. Karmazyn, and E. G. Noble, “Exercise improves postischemic cardiac function in males but not females: consequences of a novel sex-specific heat shock protein 70 response,” Circulation Research, vol. 90, no. 8, pp. 911–917, 2002.
View at: Publisher Site | Google Scholar
M. Amrani, N. Latif, K. Morrison et al., “Relative induction of heat shock protein in coronary endothelial cells and cardiomyocytes: implications for myocardial protection,” Journal of Thoracic and Cardiovascular Surgery, vol. 115, no. 1, pp. 200–209, 1998.
View at: Publisher Site | Google Scholar
J. P. Leger, F. M. Smith, and R. W. Currie, “Confocal microscopic localization of constitutive and heat shock-induced proteins HSP70 and HSP27 in the rat heart,” Circulation, vol. 102, no. 14, pp. 1703–1709, 2000.
View at: Google Scholar
E. Tarricone, C. Scapin, M. Vitadello et al., “Cellular distribution of Hsp70 expression in rat skeletal muscles. Effects of moderate exercise training and chronic hypoxia,” Cell Stress and Chaperones, vol. 13, no. 4, pp. 483–495, 2008.
View at: Publisher Site | Google Scholar
K. I. Milne, S. Wolff, and E. G. Noble, “Myocardial accumulation and localization of the inducible 70-KDa heat chock protein, Hsp 70, following exercise,” Journal of Applied Physiology, vol. 113, no. 6, pp. 853–860, 2012.
View at: Google Scholar
J. J. Whyte and M. Harold Laughlin, “The effects of acute and chronic exercise on the vasculature,” Acta Physiologica, vol. 199, no. 4, pp. 441–450, 2010.
View at: Publisher Site | Google Scholar
S. Li, R. S. Piotrowicz, E. G. Levin, Y. J. Shyy, and S. Chien, “Fluid shear stress induces the phosphorylation of small heat shock proteins in vascular endothelial cells,” American Journal of Physiology, vol. 271, no. 3, pp. C994–C1000, 1996.
View at: Google Scholar
G. García-Cardeña, R. Fan, V. Shah et al., “Dynamic activation of endothelial nitric oxide synthase by Hsp90,” Nature, vol. 392, no. 6678, pp. 821–824, 1998.
View at: Publisher Site | Google Scholar
A. R. Brooks, P. I. Lelkes, and G. M. Rubanyi, “Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow,” Physiological Genomics, vol. 9, no. 1, pp. 27–41, 2002.
View at: Google Scholar
S. A. Loktionova and A. E. Kabakov, “Protein phosphatase inhibitors and heat preconditioning prevent Hsp27 dephosphorylation, F-actin disruption and deterioration of morphology in ATP-depleted endothelial cells,” FEBS Letters, vol. 433, no. 3, pp. 294–300, 1998.
View at: Google Scholar
W. Pipkin, J. A. Johnson, T. L. Creazzo, J. Burch, P. Komalavilas, and C. Brophy, “Localization, macromolecular associations, and function of the small heat shock-related protein HSP20 in rat heart,” Circulation, vol. 107, no. 3, pp. 469–476, 2003.
View at: Publisher Site | Google Scholar
H. Jerius, D. R. Karolyi, J. S. Mondy et al., “Endothelial-dependent vasodilation is associated with increases in the phosphorylation of a small heat shock protein (HSP20),” Journal of Vascular Surgery, vol. 29, no. 4, pp. 678–684, 1999.
View at: Google Scholar
C. M. Rembold, D. B. Foster, J. D. Strauss, C. J. Wingard, and J. E. van Eyk, “cGMP-mediated phosphorylation of heat shock protein 20 may cause smooth muscle relaxation without myosin light chain dephosphorylation in swine carotid artery,” Journal of Physiology, vol. 524, no. 3, pp. 865–878, 2000.
View at: Google Scholar
E. C. McLemore, D. J. Tessier, C. R. Flynn et al., “Transducible recombinant small heat shock-related protein, HSP20, inhibits vasospasm and platelet aggregation,” Surgery, vol. 136, no. 3, pp. 573–578, 2004.
View at: Publisher Site | Google Scholar
S. Salinthone, M. Tyagi, and W. T. Gerthoffer, “Small heat shock proteins in smooth muscle,” Pharmacology and Therapeutics, vol. 119, no. 1, pp. 44–54, 2008.
View at: Publisher Site | Google Scholar
I. K. Kim, T. G. Park, Y. H. Kim, J. W. Cho, B. S. Kang, and C. Y. Kim, “Heat-shock response is associated with enhanced contractility of vascular smooth muscle in isolated rat aorta,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 369, no. 4, pp. 402–407, 2004.
View at: Publisher Site | Google Scholar
K. A. Pritchard, A. W. Ackerman, E. R. Gross et al., “Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase,” Journal of Biological Chemistry, vol. 276, no. 21, pp. 17621–17624, 2001.
View at: Publisher Site | Google Scholar
W. Insull Jr., “The pathology of atherosclerosis: plaque development and plaque responses to medical treatment,” American Journal of Medicine, vol. 122, supplement 1, pp. S3–S14, 2009.
View at: Publisher Site | Google Scholar
M. Simionescu and F. Antohe, “Functional ultrastructure of the vascular endothelium: changes in various pathologies,” Handbook of Experimental Pharmacology, no. 176, pp. 41–69, 2006.
View at: Google Scholar
A. A. Arce-Esquivel, K. V. Kreutzer, J. W. Rush, J. R. Turk, and M. H. Laughlin, “Exercise does not attenuate early CAD progression in a pig model,” Medicine & Science in Sports & Exercise, vol. 44, no. 1, pp. 27–38, 2012.
View at: Google Scholar
D. P. Hajjar and M. E. Haberland, “Lipoprotein trafficking in vascular cells: molecular Trojan horses and cellular saboteurs,” Journal of Biological Chemistry, vol. 272, no. 37, pp. 22975–22978, 1997.
View at: Publisher Site | Google Scholar
D. G. Harrison, J. Widder, I. Grumbach, W. Chen, M. Weber, and C. Searles, “Endothelial mechanotransduction, nitric oxide and vascular inflammation,” Journal of Internal Medicine, vol. 259, no. 4, pp. 351–363, 2006.
View at: Publisher Site | Google Scholar
M. J. Crabtree, A. L. Tatham, Y. Al-Wakeel et al., “Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterineNOS stoichiometry and biopterin redox status insights from cells with TET-regulated GTP cyclohydrolase I expression,” Journal of Biological Chemistry, vol. 284, no. 2, pp. 1136–1144, 2009.
View at: Publisher Site | Google Scholar
J. S. Beckman, T. W. Beckman, J. Chen, P. A. Marshall, and B. A. Freeman, “Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 4, pp. 1620–1624, 1990.
View at: Google Scholar
A. Tedgui and Z. Mallat, “Anti-inflammatory mechanisms in the vascular wall,” Circulation Research, vol. 88, no. 9, pp. 877–887, 2001.
View at: Google Scholar
A. Kumar, Y. Takada, A. M. Boriek, and B. B. Aggarwal, “Nuclear factor-κB: its role in health and disease,” Journal of Molecular Medicine, vol. 82, no. 7, pp. 434–448, 2004.
View at: Google Scholar
B. Rinaldi, P. Romagnoli, S. Bacci et al., “Inflammatory events in a vascular remodeling model induced by surgical injury to the rat carotid artery,” British Journal of Pharmacology, vol. 147, no. 2, pp. 175–182, 2006.
View at: Publisher Site | Google Scholar
S. L. DeMeester, T. G. Buchman, and J. P. Cobb, “The heat shock paradox: does NF-κB determine cell fate?” The FASEB Journal, vol. 15, no. 1, pp. 270–274, 2001.
View at: Publisher Site | Google Scholar
U. Senftleben and M. Karin, “The IKK/NF-κB pathway,” Critical Care Medicine, vol. 30, supplement 1, pp. S18–S26, 2002.
View at: Google Scholar
R. Zhao and G. X. Shen, “Involvement of heat shock factor-1 in glycated LDL-induced upregulation of plasminogen activator inhibitor-1 in vascular endothelial cells,” Diabetes, vol. 56, no. 5, pp. 1436–1444, 2007.
View at: Publisher Site | Google Scholar
G. Wick, R. Kleindienst, G. Schett, A. Amberger, and Q. Xu, “Role of heat shock protein 65/60 in the pathogenesis of atherosclerosis,” International Archives of Allergy and Immunology, vol. 107, no. 1–3, pp. 130–131, 1995.
View at: Google Scholar
Y. Chen, T. S. Voegeli, P. P. Liu, E. G. Noble, and R. W. Curie, “Heat stock paradox and a new role of heat shock proteins and their receptors as anti-inflammation targets,” Inflammation and Allergy, vol. 6, no. 2, pp. 91–100, 2007.
View at: Publisher Site | Google Scholar
B. Henderson and A. G. Pockley, “Proteotoxic stress and circulating cell stress proteins in the cardiovascular diseases,” Cell Stress and Chaperones, vol. 17, no. 3, pp. 303–311, 2012.
View at: Google Scholar
M. Gleeson, N. C. Bishop, D. J. Stensel, M. R. Lindley, S. S. Mastana, and M. A. Nimmo, “The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease,” Nature Reviews Immunology, vol. 11, no. 9, pp. 607–615, 2011.
View at: Publisher Site | Google Scholar
Y. Xie, C. Chen, M. A. Stevenson, D. A. Hume, P. E. Auron, and S. K. Calderwood, “NF-IL6 and HSF1 have mutually antagonistic effects on transcription in monocytic cells,” Biochemical and Biophysical Research Communications, vol. 291, no. 4, pp. 1071–1080, 2002.
View at: Publisher Site | Google Scholar
T. Uchiyama, H. Atsuta, T. Utsugi et al., “HSF1 and constitutively active HSF1 improve vascular endothelial function (heat shock proteins improve vascular endothelial function),” Atherosclerosis, vol. 190, no. 2, pp. 321–329, 2007.
View at: Publisher Site | Google Scholar
A. K. De, K. M. Kodys, B. S. Yeh, and C. Miller-Graziano, “Exaggerated human monocyte IL-10 concomitant to minimal TNF-α induction by heat-shock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus,” Journal of Immunology, vol. 165, no. 7, pp. 3951–3958, 2000.
View at: Google Scholar
L. Wieten, F. Broere, R. van der Zee, E. K. Koerkamp, J. Wagenaar, and W. van Eden, “Cell stress induced HSP are targets of regulatory T cells: a role for HSP inducing compounds as anti-inflammatory immuno-modulators?” FEBS Letters, vol. 581, no. 19, pp. 3716–3722, 2007.
View at: Publisher Site | Google Scholar
C. M. Cahill, W. R. Waterman, Y. Xie, P. E. Auron, and S. K. Calderwood, “Transcriptional repression of the prointerleukin 1β gene by heat shock factor 1,” Journal of Biological Chemistry, vol. 271, no. 40, pp. 24874–24879, 1996.
View at: Google Scholar
I. Kim, H. M. Shin, and W. Baek, “Heat-shock response is associated with decreased production of interleukin-6 in murine aortic vascular smooth muscle cells,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 371, no. 1, pp. 27–33, 2005.
View at: Publisher Site | Google Scholar
A. G. Pockley, S. K. Calderwood, and G. Multhoff, “The atheroprotective properties of Hsp70: a role for Hsp70-endothelial interactions?” Cell Stress and Chaperones, vol. 14, no. 6, pp. 545–553, 2009.
View at: Publisher Site | Google Scholar
S. D. House and P. T. Guidon, “Effects of heat shock, stannous chloride, and gallium nitrate on the rat inflammatory response,” Cell Stress and Chaperones, vol. 6, no. 2, pp. 164–171, 2001.
View at: Google Scholar
N. Nakabe, S. Kokura, M. Shimozawa et al., “Hyperthermia attenuates TNF-alpha-induced up regulation of endothelial cell adhesion molecules in human arterial endothelial cells,” International Journal of Hyperthermia, vol. 23, no. 3, pp. 217–224, 2007.
View at: Publisher Site | Google Scholar
P. Mehlen, C. Kretz-Remy, X. Préville, and A. P. Arrigo, “Human hsp27, Drosophila hsp27 and human αB-crystallin expression-mediated increase in glutathione is essential for the protective activity of these proteins against TNFα-induced cell death,” The EMBO Journal, vol. 15, no. 11, pp. 2695–2706, 1996.
View at: Google Scholar
S. H. Baek, J. N. Min, E. M. Park et al., “Role of small heat shock protein HSP25 in radioresistance and glutathione-redox cycle,” Journal of Cellular Physiology, vol. 183, no. 1, pp. 100–107, 2000.
View at: Google Scholar
J. P. Gratton, J. Fontana, D. S. O'Connor, G. García-Cardeña, T. J. McCabe, and W. C. Sessa, “Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and caveolin-1 complex in vitro: evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1,” Journal of Biological Chemistry, vol. 275, no. 29, pp. 22268–22272, 2000.
View at: Publisher Site | Google Scholar
A. Brouet, P. Sonveaux, C. Dessy, J. L. Balligand, and O. Feron, “Hsp90 ensures the transition from the early Ca²⁺-dependent to the late phosphorylation-dependent activation of the endothelial nitric-oxide synthase in vascular endothelial growth factor-exposed endothelial cells,” Journal of Biological Chemistry, vol. 276, no. 35, pp. 32663–32669, 2001.
View at: Publisher Site | Google Scholar
M. B. Harris, B. M. Mitchell, S. G. Sood, R. C. Webb, and R. C. Venema, “Increased nitric oxide synthase activity and Hsp90 association in skeletal muscle following chronic exercise,” European Journal of Applied Physiology, vol. 104, no. 5, pp. 795–802, 2008.
View at: Publisher Site | Google Scholar
E. A. Kaperonis, C. D. Liapis, J. D. Kakisis, D. Dimitroulis, and V. G. Papavassiliou, “Inflammation and atherosclerosis,” European Journal of Vascular and Endovascular Surgery, vol. 31, no. 4, pp. 386–393, 2006.
View at: Publisher Site | Google Scholar
C. Paul, F. Manero, S. Gonin, C. Kretz-Remy, S. Virot, and A. P. Arrigo, “Hsp27 as a negative regulator of cytochrome C release,” Molecular and Cellular Biology, vol. 22, no. 3, pp. 816–834, 2002.
View at: Google Scholar
V. L. Gabai, K. Mabuchi, D. D. Mosser, and M. Y. Sherman, “Hsp72 and stress kinase C-jun N-terminal kinase regulate the Bid-dependent pathway in tumor necrosis factor-induced apoptosis,” Molecular and Cellular Biology, vol. 22, no. 10, pp. 3415–3424, 2002.
View at: Publisher Site | Google Scholar
J. M. Bruey, C. Ducasse, P. Bonniaud et al., “Hsp27 negatively regulates cell death by interacting with cytochrome C,” Nature Cell Biology, vol. 2, no. 9, pp. 645–652, 2000.
View at: Publisher Site | Google Scholar
H. M. Beere, B. B. Wolf, K. Cain et al., “Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome,” Nature Cell Biology, vol. 2, no. 8, pp. 469–475, 2000.
View at: Publisher Site | Google Scholar
L. Ravagnan, S. Gurbuxani, S. A. Susin et al., “Heat-shock protein 70 antagonizes apoptosis-inducing factor,” Nature Cell Biology, vol. 3, no. 9, pp. 839–843, 2001.
View at: Publisher Site | Google Scholar
V. L. Gabai, A. B. Meriin, J. A. Yaglom, J. Y. Wei, D. D. Mosser, and M. Y. Sherman, “Suppression of stress kinase JNK is involved in HSP72-mediated protection of myogenic cells from transient energy deprivation. HSP72 alleviates the stress-induced inhibition of JNK dephosphorylation,” Journal of Biological Chemistry, vol. 275, no. 48, pp. 38088–38094, 2000.
View at: Publisher Site | Google Scholar
P. Mehlen, K. Schulze-Osthoff, and A. P. Arrigo, “Small stress proteins as novel regulators of apoptosis. Heat shock protein 27 blocks Fas/APO-1- and staurosporine-induced cell death,” Journal of Biological Chemistry, vol. 271, no. 28, pp. 16510–16514, 1996.
View at: Publisher Site | Google Scholar
N. J. Clemons, K. Buzzard, R. Steel, and R. L. Anderson, “Hsp72 inhibits Fas-mediated apoptosis upstream of the mitochondria in type II cells,” Journal of Biological Chemistry, vol. 280, no. 10, pp. 9005–9012, 2005.
View at: Publisher Site | Google Scholar
K. J. Park, R. B. Gaynor, and Y. T. Kwak, “Heat shock protein 27 association with the IκB kinase complex regulates tumor necrosis factor α-induced NF-κB activation,” Journal of Biological Chemistry, vol. 278, no. 37, pp. 35272–35278, 2003.
View at: Publisher Site | Google Scholar
Y. Chen, A. P. Arrigo, and R. W. Currie, “Heat shock treatment suppresses angiotensin II-induced activation of NF-κB pathway and heart inflammation: a role for IKK depletion by heat shock?” American Journal of Physiology, vol. 287, no. 3, pp. H1104–H1114, 2004.
View at: Publisher Site | Google Scholar
Y. G. Weiss, Z. Bromberg, N. Raj et al., “Enhanced heat shock protein 70 expression alters proteasomal degradation of IκB kinase in experimental acute respiratory distress syndrome,” Critical Care Medicine, vol. 35, no. 9, pp. 2128–2138, 2007.
View at: Publisher Site | Google Scholar
M. T. Schell, A. L. Spitzer, J. A. Johnson, D. Lee, and H. W. Harris, “Heat shock inhibits NF-κB activation in a dose- and time-dependent manner,” Journal of Surgical Research, vol. 129, no. 1, pp. 90–93, 2005.
View at: Publisher Site | Google Scholar
M. der Perng, L. Cairns, P. van den IJssel, A. Prescott, A. M. Hutcheson, and R. A. Quinlan, “Intermediate filament interactions can be altered by HSP27 and αB-crystallin,” Journal of Cell Science, vol. 112, pp. 2099–2112, 1999.
View at: Google Scholar
H. Wei, W. Campbell, and R. S. van der Heide, “Heat shock-induced cardioprotection activates cytoskeletal-based cell survival pathways,” American Journal of Physiology, vol. 291, no. 2, pp. H638–H647, 2006.
View at: Publisher Site | Google Scholar
J. Amour, A. K. Brzezinska, Z. Jager et al., “Hyperglycemia adversely modulates endothelial nitric oxide synthase during anesthetic preconditioning through tetrahydrobiopterin- and heat shock protein 90-mediated mechanisms,” Anesthesiology, vol. 112, pp. 576–585, 2010.
View at: Google Scholar
Y. Uchida, K. Takeshita, K. Yamamoto et al., “Stress augments insulin resistance and prothrombotic state: role of visceral adipose-derived monocyte chemoattractant protein-1,” Diabetes, vol. 61, pp. 1552–1561, 2012.
View at: Google Scholar
D. F. Pengiran Burut, A. Borai, C. Livingstone, and G. Ferns, “Serum heat shock protein 27 antigen and antibody levels appear to be related to the macrovascular complications associated with insulin resistance: a pilot study,” Cell Stress and Chaperones, vol. 15, no. 4, pp. 379–386, 2010.
View at: Publisher Site | Google Scholar
Y. Huang, Y. Hu, W. Mai et al., “Plasma oxidized low-density lipoprotein is an independent risk factor in young patients with coronary artery disease,” Disease Markers, vol. 31, pp. 295–301, 2011.
View at: Google Scholar
S. Ren and G. X. Shen, “Impact of antioxidants and HDL on glycated LDL-induced generation of fibrinolytic regulators from vascular endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 20, no. 6, pp. 1688–1693, 2000.
View at: Google Scholar
G. Bellomo, E. Maggi, M. Poli, F. G. Agosta, P. Bollati, and G. Finardi, “Antoantibodies against oxidatively modified low-density lipoproteins in NIDDM,” Diabetes, vol. 44, no. 1, pp. 60–66, 1995.
View at: Google Scholar
R. Zhao, X. Ma, X. Xie, and G. X. Shen, “Involvement of NADPH oxidase in oxidized LDL-induced upregulation of heat shock factor-1 and plasminogen activator inhibitor-1 in vascular endothelial cells,” American Journal of Physiology, vol. 297, no. 1, pp. E104–E111, 2009.
View at: Publisher Site | Google Scholar
S. C. Sharma, “Platelet adhesiveness, plasma fibrinogen and fibrinolytic activity in diabetes mellitus,” Thrombosis and Haemostasis, vol. 45, no. 1, article 100, 1981.
View at: Google Scholar
G. Pralong, T. Calandra, M. P. Glauser et al., “Plasminogen activator inhibitor 1: a new prognostic marker in septic shock,” Thrombosis and Haemostasis, vol. 61, no. 3, pp. 459–462, 1989.
View at: Google Scholar
X. Xu, H. Wang, Z. Wang, and W. Xiao, “Plasminogen activator inhibitor-1 promotes inflammatory process induced by cigarette smoke extraction or lipopolysaccharides in alveolar epithelial cells,” Experimental Lung Research, vol. 35, no. 9, pp. 795–805, 2009.
View at: Publisher Site | Google Scholar
S. K. Roy Chowdhury, G. V. Sangle, X. Xie, G. L. Stelmack, A. J. Halayko, and G. X. Shen, “Effects of extensively oxidized low-density lipoprotein on mitochondrial function and reactive oxygen species in porcine aortic endothelial cells,” American Journal of Physiology, vol. 298, no. 1, pp. E89–E98, 2010.
View at: Publisher Site | Google Scholar
G. V. Sangle, S. K. R. Chowdhury, X. Xie, G. L. Stelmack, A. J. Halayko, and G. X. Shen, “Impairment of mitochondrial respiratory chain activity in aortic endothelial cells induced by glycated low-density lipoprotein,” Free Radical Biology and Medicine, vol. 48, no. 6, pp. 781–790, 2010.
View at: Publisher Site | Google Scholar
X. Xie, R. Zhao, and G. X. Shen, “Influence of delphinidin-3-glucoside on oxidized low density lipoprotein-indued oxidative stress and apoptosis in cultured endothelial cells,” Journal of Agricultural and Food Chemistry, vol. 60, pp. 1850–1856, 2012.
View at: Google Scholar
A. Rabinovitch, “Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM: therapeutic intervention by immunostimulation?” Diabetes, vol. 43, no. 5, pp. 613–621, 1995.
View at: Google Scholar
M. D. S. Krause and P. I. de Bittencourt Jr., “Type 1 diabetes: can exercise impair the autoimmune event? The L-arginine/glutamine coupling hypothesis,” Cell Biochemistry and Function, vol. 26, no. 4, pp. 406–433, 2008.
View at: Publisher Site | Google Scholar
A. P. Nácul, C. D. Andrade, P. Schwarz, P. I. H. de Bittencourt, and P. M. Spritzer, “Nitric oxide and fibrinogen in polycystic ovary syndrome: associations with insulin resistance and obesity,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 133, no. 2, pp. 191–196, 2007.
View at: Publisher Site | Google Scholar
P. Newsholme, E. P. Haber, S. M. Hirabara et al., “Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity,” Journal of Physiology, vol. 583, no. 1, pp. 9–24, 2007.
View at: Publisher Site | Google Scholar
J. E. Yardley, G. P. Kenny, B. A. Perkins et al., “Effects of performing resistance exercise before versus after aerobic exercise on glycemia in type 1 diabetes,” Diabetes Care, vol. 35, pp. 669–675, 2012.
View at: Google Scholar
M. Atalay, N. K. J. Oksala, D. E. Laaksonen et al., “Exercise training modulates heat shock protein response in diabetic rats,” Journal of Applied Physiology, vol. 97, no. 2, pp. 605–611, 2004.
View at: Publisher Site | Google Scholar

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Copyright © 2012 Earl G. Noble and Garry X. Shen. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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