Table of Contents Author Guidelines Submit a Manuscript
Oxidative Medicine and Cellular Longevity
Volume 2013 (2013), Article ID 104308, 10 pages
http://dx.doi.org/10.1155/2013/104308
Review Article

Nrf2 and Cardiovascular Defense

Laboratory of Systems Physiology, Department of Kinesiology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA

Received 11 January 2013; Revised 15 March 2013; Accepted 19 March 2013

Academic Editor: Hye-Youn Cho

Copyright © 2013 Reuben Howden. 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.

Abstract

The cardiovascular system is susceptible to a group of diseases that are responsible for a larger proportion of morbidity and mortality than any other disease. Many cardiovascular diseases are associated with a failure of defenses against oxidative stress-induced cellular damage and/or death, leading to organ dysfunction. The pleiotropic transcription factor, nuclear factor-erythroid (NF-E) 2-related factor 2 (Nrf2), regulates the expression of antioxidant enzymes and proteins through the antioxidant response element. Nrf2 is an important component in antioxidant defenses in cardiovascular diseases such as atherosclerosis, hypertension, and heart failure. Nrf2 is also involved in protection against oxidant stress during the processes of ischemia-reperfusion injury and aging. However, evidence suggests that Nrf2 activity does not always lead to a positive outcome and may accelerate the pathogenesis of some cardiovascular diseases (e.g., atherosclerosis). The precise conditions under which Nrf2 acts to attenuate or stimulate cardiovascular disease processes are unclear. Further studies on the cellular environments related to cardiovascular diseases that influence Nrf2 pathways are required before Nrf2 can be considered a therapeutic target for the treatment of cardiovascular diseases.

1. Introduction

Cardiovascular diseases contribute more to morbidity and mortality than any other group of diseases in the developed world [1]. Oxidative stress is an important component in the pathogenesis of many cardiovascular disorders, including atherosclerosis [2, 3], hypertension [4], heart failure [5], and ischemia/reperfusion injury [68]. Sources of potentially damaging reactive oxygen species (ROS) leading to oxidative stress have been extensively reviewed (e.g. [911]) and include, but are not limited to, mitochondrial electron transport chain inefficiencies, NADPH oxidase and ubiquitous xanthine oxidase activity, and metallic ions released during cell lysis. This suggests that the activation of antioxidant defenses has an important role in reducing oxidant-induced cellular damage. However, cellular damage or death can still result, leading to organ dysfunction, when cellular antioxidant defenses are overwhelmed by excess ROS production [12].

A well-established and critical component to cellular antioxidant defense mechanisms is expression of direct ROS scavenging enzymes, phase II detoxification enzymes, and other detoxification proteins bearing antioxidant response elements (AREs) in their promoter regions. A principal regulator of the ARE is the highly conserved transcription factor nuclear factor-erythroid (NF-E) 2-related factor 2 (NRF2 for human, Nrf2 for mouse and rat), which is a member of the Cap “n” collar family of transcription factors (more details on Nrf2 are provided elsewhere in this special issue). Nrf2 induces transcriptional activation of a number of ARE-bearing antioxidants, including NAD(P)H dehydrogenase (quinone 1) (NQO1), superoxide dismutases (SODs), and glutathione peroxidases (GPx). Many of the Nrf2 regulated enzymes are essential in the pathogenesis of cardiovascular diseases [13]. However, there exists evidence for both beneficial and detrimental effects of Nrf2 activation in the cardiovascular system. Further investigation is required to better understand the range of interactions between Nrf2 and the cardiovascular system, which could have profound effects on the pathogenesis of cardiovascular diseases. Therefore, the purpose of this review is to discuss the current evidence for a role of Nrf2 in a selection of prominent cardiovascular pathologies.

2. Nrf2 and Atherosclerosis

Several vascular disease processes are associated with oxidative stress, and therefore suboptimal antioxidant defenses may increase patient risk and accelerate disease progression [14]. Atherosclerosis is an inflammatory disease [15] characterized by endothelial infiltration and accumulation of oxidized low-density lipoproteins (LDLs), physical damage to the endothelium (e.g. turbulent blood flow, hypertension, and/or toxins from cigarette smoking), and/or infection (e.g. HIV). This process leads to atherosclerotic lesions, compromised blood vessel diameter, and increased risk of ischemia, which is a major concern especially in the myocardium.

Interestingly, evidence suggests that susceptibility to atheroma formation is not uniform throughout the vascular system. Several studies suggest that shear stress generated by oscillatory, nonunidirectional, and turbulent blood flow, for example at bifurcations or points of vessel branching, results in atheroma-prone regions [16, 17], increasing the risk of atherosclerosis development. Conversely, atheromas are less likely to form in vascular regions only exposed to unidirectional laminar blood flow [16, 18]. It is well established that laminar vascular wall shear stress stimulates the release of nitric oxide (NO), known for its protective role against atherosclerosis (see [19] for review). However, when blood flow becomes oscillatory (e.g. high flow rates, stenosis, or vessel branching), shear stress on the vascular wall is inconsistent. This reduces NO production and increases superoxide release, which leads to enhanced oxidative stress and atherosclerosis progression [20]. Therefore, laminar versus oscillatory blood flow may be responsible for the apparent confusion regarding the role of Nrf2 in the pathogenesis of atherosclerosis. It is becoming clear that laminar blood flow promotes antiatherogenic activation of Nrf2, and oscillatory blood flow suppresses Nrf2 activation, creating a proatherogenic environment [21, 22]. However, specific blood flow characteristics, in relation to atherosclerosis progression, should be investigated in greater detail to improve the understanding of the interaction between blood flow, Nrf2, and atherosclerosis susceptibility.

3. Nrf2 as an Antiatherogenic Factor

It is becoming increasingly apparent that Nrf2 is important to vascular integrity and long-term endothelial function, for example, sustained release of NO and protection from apoptosis [2329]. Conversely, specific changes in vascular physiology that are related to Nrf2 can lead to increased susceptibility to atheroma development, such as increases in oxidative stress leading to oxidation of LDLs, reduced NO production, and increased levels of superoxide [20].

One important stage of atherosclerotic plaque formation is a well-established endothelial infiltration by macrophages and foam cell formation following macrophage absorption of accumulated LDLs. In mice, Nrf2 is an important component in this process, since macrophages exposed to oxidized LDLs (oxLDL) increased Nrf2 expression in response, which indirectly protected macrophages from oxLDL-mediated injury via phase II antioxidant enzyme activity [30]. Moreover, absence of Nrf2 in high fat diet myeloid-derived macrophages [31] or LDL receptor deficient myeloid-derived macrophages [32] increased foam cell formation and atherosclerosis progression, further suggesting that Nrf2 is important in resistance to atherosclerosis.

Increases in Nrf2 expression at this stage of atherosclerosis development is significant because of downstream effects on heme oxygenase-1 (HO-1), which produces antiatherogenic reductions foam cell formation [3336]. Moreover, atherosclerosis was accelerated in HO-1 absent/apolipoprotein E-deficient ( ) mice [37]. The mouse strain is a well-established model for atherosclerosis [38, 39]. In addition to its antioxidant properties, HO-1 protects against inflammation in vascular tissue [33, 40, 41] and has been reported to act in an atheroprotective manner through this mechanism [42, 43]. Since oxidative stress and inflammation are known to be important at all stages of atherosclerosis development [2, 44], these data suggest a central role for HO-1 in atherosclerosis pathophysiology.

In mice, HO-1 has also been reported to suppress atherosclerotic lesion formation by reducing oxLDL-induced transmigration of monocytes, and the reverse was found when HO-1 was inhibited [34]. In addition to oxLDL activated increases in HO-1 expression through Nrf2, other Nrf2 downstream targets appear to play a role in this process, like glutathione-cysteine ligase modifying subunit and NQO1, both of which have been associated with protection against atherosclerosis [26]. In adolescents, low serum glutathione was an independent risk factor for parental coronary heart disease risk [45]. Moreover, low GPx levels, for which glutathione is a cofactor, combined with low high-density lipoprotein levels may be partly responsible for increased atherosclerosis-related mortality rates in humans [46]. Nrf2 was identified as an important regulator of GPx in mice [47], and therefore taken together, these data demonstrate that Nrf2 is an important component in protection against the pathogenesis of atherosclerosis.

HO-1 may also offer protection from atherosclerosis-related morbidity and/or mortality at more advanced stages of the disease by promoting atherosclerotic plaque stability. It has been suggested that matrix metalloproteinase 9 (MMP9) levels are linked to plaque destabilization [48, 49], which are important events in acute constriction of vessel blood flow and sudden cardiac or cerebral events. Interestingly, an atheroprotective role for HO-1 may be partially associated with MMP9 suppression to maintain or improve plaque stability [50], potentially avoiding an acute, life-threatening coronary or cerebral event. These data present convincing evidence for the importance of Nrf2 and its downstream targets in protection against atherosclerotic plaque formation or stability.

In addition to atherosclerotic processes, Nrf2 expression may also be induced by extrinsic factors, leading to protection against the disease. For example, activation of Nrf2 by dosing mice with the cruciferous vegetable extract sulforaphane had an anti-inflammatory effect on atherosusceptible endothelial cells [51], although the effect of the sulforaphane dose used in their study on Nrf2 expression was not assessed. Therefore, it is possible that in this case, Nrf2 was not activated and sulforaphane induced other anti-inflammatory factors. However, it should be noted that sulforaphane has been reported to induce expression of antioxidant enzymes regulated by Nrf2 [5254]. Furthermore, increased Nrf2 message and nuclear NRF2 were found with sulforaphane-treated mice in a model of respiratory syncytial virus disease [55].

4. Nrf2 as a Proatherogenic Factor

Interestingly, Nrf2 has been reported to be proatherogenic in an elegant study comparing atherosclerotic plaque formation in mice that were either Nrf2 sufficient or deficient, combined with either a 10- or 20-week high fat diet [56]. mice developed significantly less aortic plaque area and loss of vessel wall elasticity compared to mice, which was reported to occur in a sex-dependent manner [57]. Moreover, this effect appeared to be partly dependent on diet, which increases the urgency for diet modification in the general population, especially in low socioeconomic regions where diet-related susceptibility to atherosclerosis, among other cardiovascular diseases, is known to be higher [58]. However, the study of Barajas et al. suggests independent actions of Nrf2 and HO-1 in atherosclerosis. In mice, Nrf2 deletion resulted in atherosclerosis suppression [57], but with HO-1 deletion the atherosclerosis was accelerated [37]. Considering the regulation of HO-1 by Nrf2, this illustrates the current confusion regarding the role of Nrf2 in atherosclerosis.

The paradox between compromised antioxidant defenses in mice and lower aortic atheroma area could be associated with a reduction in macrophage uptake of oxLDL and foam cell formation, as previously discussed. The scavenger protein CD36 regulates macrophage uptake of oxLDL, and normal oxLDL-induced increases in CD36 expression were not found in macrophages [59]. This suggests that in atherosclerosis development, inhibition of macrophage uptake of oxLDL is more important than antioxidant capacity, both of which are regulated by Nrf2. This highlights the current confusion regarding the role of Nrf2 in atherosclerosis development. In the previous section, discussion of Nrf2 as an antiatherogenic factor involved increases in Nrf2 expression leading to lower foam cell formation in the presence of HO-1 [33, 35, 36, 60]. However, these opposing influences of Nrf2 on atherosclerosis development operated via different mechanisms and the degree of interindividual atherosclerosis patient difference in the prominence of one mechanism or the other are not known but may be critical in understanding the progression of this disease.

In addition to Nrf2-mediated upregulation of scavenger proteins promoting atherosclerosis progression, other factors regulated by Nrf2 may add to a proatherosclerotic effect. Activating transcription factor 4 (ATF4), known to control vascular endothelial growth factor, stimulates plaque formation by recruiting monocytes to the atherogenic region [61, 62]. Recently, crosstalk between Nrf2 and ATF4 was demonstrated in endothelial cells [63], further suggesting a proatherogenic effect of Nrf2. However, it is beyond the scope of this review to discuss all factors that interact with Nrf2 in the pathogenesis of atherosclerosis, principally because Nrf2 is a highly influential gene, especially when enhanced oxidative stress is present. For example, Nrf2 is known to interact with other well-established pro-atherogenic factors, including vascular cell adhesion molecule 1 [64], NQO1 [65], and interleukin-1 [66]. However, it should be noted that NQO1 has also been reported as both an anti- and proatherogenic factor and therefore improved the understanding of the role of NQO1 in atherosclerosis susceptibility that may lead to clarification of Nrf2 influences on this process. Nonetheless, it is possible through multiple mechanisms that Nrf2 produces competing effects on the pathophysiology of atherosclerosis, which highlights the complexity of this disease.

5. Nrf2 and Ischemia-Reperfusion Injury

It has long been recognized that compromised blood flow and cellular perfusion leading to ischemia has major injurious effects on the organ in question. Prominent examples include stroke, myocardial infarction, and organ transplantation. Therefore, reestablishment of blood flow as quickly as possible is a primary clinical goal in ischemia. However, an acute restoration of blood flow to an ischemic region can lead to an enhanced degree of injury as a consequence of oxidative stress compared to the initial period of ischemia.

The myocardium is particularly vulnerable to ischemic injury, because oxygen uptake at any given time during cellular perfusion is around 80%, and therefore cardiac myocytes are unable to significantly increase percent oxygen uptake from arterial blood when blood flow is severely compromised by vascular constriction (e.g. atherosclerotic plaque thrombosis or vasospasm, leading to ischemia). When blood flow is restored however, a substantial inflammatory response is induced [67], significantly increasing oxidative stress, which can overwhelm antioxidant defenses resulting in cardiac dysfunction from cell damage or death. This process makes Nrf2 an important candidate for resistance to ischemia-reperfusion injury, but there is little information about its role in this situation.

Nonetheless, in rat cardiac H9c2 cells, simulated ischemia reperfusion (10 hrs hypoxia, followed by 16 hrs normoxia) resulted in a significant increase in intracellular ROS levels. Under the same conditions, H9c2 cells were treated with the phase II antioxidant enzyme inducer D3T, which was accompanied by a significant reduction in intracellular ROS levels. In these cells, increases in Nrf2 mRNA and protein were found, suggesting that Nrf2 may be important in controlling intracellular ROS levels following ischemia reperfusion [68]. Conversely, in rat hearts, 30 minutes of left anterior descending coronary artery occlusion resulted in a reduction in Nrf2 nuclear protein, which was prevented by ischemic preconditioning of the myocardium [69]. This finding is very important as it suggests that in order for Nrf2 to initiate antioxidant defenses against reperfusion-induced oxidative stress, the length of the prior ischemic phase may be a critical factor. Early rescue from ischemia may attenuate Nrf2 responses to oxidative stress upon reperfusion, reducing protection from reperfusion-induced oxidative stress. Alternatively, ischemic preconditioning may act as an “early warning” signal and activate Nrf2 prior to a prolonged ischemic event. Acute activation of Nrf2 has been shown as cardioprotective following ischemia reperfusion. When mice were treated with hydrogen sulfate [70] or 4-hydroxy-2-nonenal [71] to activate Nrf2 prior to cardiac ischemia reperfusion, reduced infarct size in vivo or improved recovery time in Langendorff-perfused mouse hearts were observed respectively.

6. Nrf2 and Hypertension

While oxidative stress and hypertension appear to be related, a “chicken or the egg” scenario means that it is not clear if oxidative stress is a contributing factor to hypertension or if hypertension induces oxidative stress, even though both are likely the case. There are some convincing arguments for the latter [72], although it is possible that oxidative stress caused by preexisting disease (e.g. diabetes) could be a catalyst for hypertension [73]. Certainly, increased levels of ROS in renin-angiotensin-induced hypertension have been established [74, 75].

NADPH oxidases (NOX for human, Nox for mouse) are a significant source of ROS in cardiovascular diseases, including angiotensin II-dependent hypertension [74, 76, 77]. A number of Nox isoforms are emerging as important components in the pathophysiology of hypertension in their interaction with Nrf2. Nox1, expressed by vascular smooth muscle cells, has been reported to stimulate an increase in ROS levels during an angiotensin II-mediated pressor response [78]. Moreover, activation of Nrf2 by Nox1 has been found in response to intermittent hypoxia [79], suggesting a mechanism to attenuate oxidative stress through increases in Nrf2 expression. Vascular endothelial cells express Nox2, and increases in NOX2 levels have recently been associated with angiotensin II-mediated hypertension, endothelial dysfunction, and vascular remodeling [80]. These data suggest that increases in Nox are an important mechanism for resistance to oxidative stress in hypertension mediated by angiotensin II dysfunction.

Nrf2 may also be important in blood pressure regulation through an alternative and interesting mechanism. Nrf2 induces expression of HO-1, which has hypotensive effects when upregulated in spontaneously hypertensive rats [8183]. HO-1 is also implicit in the production of carbon monoxide (CO), in the breakdown of heme into CO, iron, and bilirubin. CO has direct vasodilatory effects [84], which appear to be independent of NO [85]. CO also inhibits the production of endothelin [86], a powerful vasoconstrictor, which is likely an important component of CO effects on vascular tone, regulated by HO-1, the expression of which is induced by Nrf2. Moreover, a number of studies have shown reduced blood pressure in response to increases in HO/CO pathway activity in spontaneously hypertensive rats [8789]. While speculative, these data suggest that Nrf2 may be important in blood pressure regulation in a capacity other than its part in antioxidant defenses.

However, the potential role for Nrf2 regulation of HO-1 in blood pressure control is not well defined and may only become important under specific conditions of oxidative stress, like exposure to lipopolysaccharide [90]. Moreover, there were no differences in basal blood pressure between and wild-type (WT) mice [91]. Li et al. also reported no significant differences between and WT mice in angiotensin II induced blood pressure elevation. However, the 16 mmHg greater response in systolic blood pressure in WT mice should not go unnoticed from a clinical perspective, suggesting a potential inhibition of hypertensive responses to angiotensin II in mice.

Nrf2 expression was upregulated in deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. This response, which was enhanced by concomitant epicatechin treatment (Nrf2 inducer), attenuated the hypertensive response [92]. However, it seems likely that this was due to increases in oxidative stress in association with hypertension, rather than a direct effect of Nrf2 on blood pressure regulation.

It is clear that Nrf2 is important, either directly or indirectly, in blood pressure regulation under specific biological environments (e.g. hypertension). However, the circumstances in which Nrf2 influences blood pressure must first be described in detail before Nrf2 can be considered as a target for blood pressure therapy in the clinical setting.

7. Nrf2 and Heart Failure

Increased oxidative stress in the diseased myocardium is a well-established phenomenon. Therefore, the potential for Nrf2 being an important factor in either prevention or slowing of pathophysiologic processes in the myocardium is high. In relation to heart failure, ROS impair cardiac function [93] and increase susceptibility to arrhythmia [94] by a direct toxic effect of increased necrosis and apoptosis [95].

Several Nrf2 downstream target genes have been associated with protection against abnormal myocardial remodeling in response to hypertension, including HO-1 [96, 97], SOD [98], and GPx [99]. Unfortunately, the role of Nrf2 in heart failure, while likely on the evidence, has not received significant attention. However, some evidence suggests that Nrf2 is protective against pathological myocardial hypertrophy and heart failure. In a mouse model of pressure overload by transverse aortic constriction, Nrf2 overexpression attenuated ROS production and hypertrophic growth in cardiomyocytes, and cardiac fibroblasts [100]. This protective effect of Nrf2 in myocardial remodeling and heart failure may be mediated through Nox4 [101], which is known to be an important regulator of reduction-oxidation (redox) signaling in many cell types including cardiomyocytes and is a major source of mitochondrial oxidative stress during pressure overload [102]. Furthermore, recent studies have demonstrated cardioprotective activation of Nrf2 by the Krebs cycle intermediate fumarate [103] and triterpenoids [104106], suggesting potentially useful treatments with fumarate derivatives or triterpenoids in patients suffering from pathological levels of oxidative stress.

However, while acute activation of Nrf2 is cardioprotective [70, 71, 107], there is accumulating evidence that chronic activation of Nrf2 may be harmful to cardiac function [108, 109] leading to pathophysiological processes and heart failure. Chronic activation of Nrf2 has been reported in association with the concept of “reductive stress” in the murine cardiac hypertrophy and heart failure model of human αB-crystallin overexpression [108]. In this model, constitutive activation of Nrf2 has been reported due to an excess of the reducing equivalents, reduced GSH and NADPH. Therefore, more information about the dynamics of acute versus chronic Nrf2 activation is required before useful treatment strategies taking advantage of this mechanism can be developed.

Moreover, there are potentially important comorbidity effects that are associated with increases in oxidative stress in the myocardium that point to Nrf2 playing a protective role. For example, cardiac myocyte insulin resistance is a key component to diabetes-induced cardiac dysfunction, and oxidative stress can exacerbate this scenario. Nrf2 expression was suppressed in diabetic mice with cardiomyopathy in late stage disease [110]. In the same study, oxidative stress in cardiomyocytes (HL-1 cells) led to depressed Nrf2 expression, extracellular signal-related kinase (ERK) activation, and a lower glucose metabolism.

This novel interaction between diabetes-related cardiomyopathy and Nrf2 could provide insight into individual susceptibility to diabetic complications in the cardiovascular system and therefore should be investigated carefully. The principle reason for this need is the current confusion regarding the influence of ERK during cellular stress. ERK signaling is important in the activation of Nrf2 in response to oxidative stress [111]. Several studies reported a protective effect of oxidative stress-induced ERK activation [112117], which is not surprising considering its importance in Nrf2 signaling. Conversely, other studies found that oxidative stress-induced upregulation of ERK was a contributing factor to apoptosis [115, 118, 119]. The precise mechanism by which ERK stimulates or prevents apoptosis is not clear. However, considering the important role of ERK in normal cell division [120], ERK-induced apoptosis has been suggested to be a mechanism to prevent uncontrolled cell proliferation under certain conditions of oxidative stress (e.g. cancer) [121], which could have negative implications when oxidative stress (e.g. hyperoxia) is not accompanied by aberrant cell proliferation.

8. Nrf2, Age, and Cardiovascular Disease

The Nrf2-Keap1 pathway is a critical element to redox homeostasis in the myocardium [109, 122]. With age, expression of several Nrf2 downstream targets declined in rats [123], and age-related arterial Nrf2 dysfunction in Macaca mulatta [124] and rats [125] has been reported. Since about 75% of cardiovascular disease associated deaths occur in people over the age of 65 years [126] and the mean global population age is increasing, this presents a significant public health concern. Especially important to consider is the large number of diseases associated with oxidative stress, not least cardiovascular diseases.

However, it may be possible to resist the reduction in Nrf2 activity associated with the aging process. In young mice, expression of myocardial Nrf2 and several downstream antioxidant target genes have been demonstrated to increase significantly after treadmill exercise comprising 90 minutes per day for 2 days [122]. Moreover, age-related reductions in Nrf2 transcriptional activity in the myocardium were reversed in mice subjected to the same treadmill exercise or following 6 weeks of moderate treadmill exercise training [127]. Exercise-induced increases in Nrf2 activity were accompanied by increased levels of antioxidants, like NQO1, HO-1, and GPx1 with corresponding attenuation of ROS status in both young and aged mice [127]. These data highlight the potential importance of habitual exercise to maintain Nrf2 function in an aging population.

Two important methods by which Nrf2 activity can be maintained or restored in the myocardium during the aging process are apparent in the literature. First, as is frequently reported, habitual exercise is beneficial for reducing risk of a host of diseases, not least cardiovascular disease and therefore represents a simple, nonpharmacological intervention to protect against age-related Nrf2 dysfunction. Second, there is a significant amount of evidence suggesting Nrf2 as a useful therapeutic target to treat oxidative stress related diseases.

9. Models for Assessing Cardiopulmonary Responses to Oxidative Stress in Rodents

Exposure of mice to high concentrations of oxygen in air (hyperoxia) for prolonged periods (3–5 days) induces significant oxidative damage to the lung similar to important diseases like acute lung injury (ALI), the more severe acute respiratory distress syndrome (ARDS), and bronchopulmonary dysplasia (BPD). Moreover, significant effects of this model on the cardiovascular system are becoming apparent. In many studies, mice or rats were group housed in exposure chambers (e.g. [128132]), or standard rodent cages were placed together in large exposure chambers (e.g. [133, 134]). This has been a successful and cost-effective method for exposing multiple animals simultaneously to investigate responses and adaptations in many biological systems, but principally in the lung. Prolonged exposure of mice to hyperoxia leads to acute alveolar inflammation and pulmonary epithelial and endothelial barrier necrosis leading to pulmonary edema and progressively compromised pulmonary gas exchange [135], which has significant effects on cardiac function [136].

Cardiovascular and pulmonary function in conscious, freely moving rodents can be monitored in real time. Electrocardiogram, blood pressure, electroencephalogram, body temperature, and activity level waveforms can be recorded continuously in animals using implantable radio-telemetry transmitters, and pulmonary function can be recorded using whole body plethysmography. Recently, combination of these methods was used to investigate the genetic component to cardiopulmonary function in a wide range of commercially available strains of mice [137]. In order for these systems to work correctly, mice must be singly housed, and therefore previous exposure chamber arrangements with group housed animals would not be appropriate for radio-telemetry or whole body plethysmography. Whole body plethysmographs have been used as hyperoxia exposure chambers (as well as a wide range of inhalants) using mice implanted with ECG telemeters, creating a model for assessing continuous cardiopulmonary responses to hyperoxia (also possible for other species, e.g. rats or rabbits) [136]. This model is a very useful tool for assessing cardiopulmonary responses to hyperoxia-induced oxidative stress and was successfully implemented to investigate the role of Nrf2 in cardiopulmonary responses to oxidants, included in this issue (refer to Howden et al.).

10. Conclusions

Nrf2 is a key component to cellular redox homeostasis in the attenuation of oxidative stress-associated pathological processes. In the cardiovascular system, patients with insufficient NRF2 levels in multiple tissues are likely susceptible to several adverse components of disease development. If Nrf2 expression is insufficient to protect against hypertension, then NRF2 is likely insufficient to protect against the resultant oxidative stress, atherosclerosis, and heart failure, highlighting the urgency for investigating Nrf2 further as a potential therapeutic target. Alternatively, there is evidence for increases in Nrf2 activity being detrimental to disease resistance and/or accelerating pathogenesis in cardiovascular diseases.

For example, while activating Nrf2 shortly before initiating ischemia reperfusion may be beneficial in terms of cardiac function outcome, there is some evidence that chronic activation of Nrf2 could be detrimental to cardiac function. Therefore, further work is required to understand the role for Nrf2 in cardiovascular pathogenesis before Nrf2 can be seriously considered as a therapeutic target for treatment of cardiovascular diseases. This is especially important when considering the increasing prevalence of multiple comorbidities in aging populations [138].

Acknowledgment

The author thanks Dr. S. Peter Magnusson for critically reading this paper.

References

  1. D. Lloyd-Jones, R. J. Adams, T. M. Brown et al., “Executive summary: heart disease and stroke statistics—2010 update: a report from the American Heart Association,” Circulation, vol. 121, no. 7, pp. 948–954, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. D. Harrison, K. K. Griendling, U. Landmesser, B. Hornig, and H. Drexler, “Role of oxidative stress in atherosclerosis,” The American Journal of Cardiology, vol. 91, no. 3, supplement, pp. 7–11, 2003. View at Publisher · View at Google Scholar · View at Scopus
  3. J. G. Park and G. T. Oh, “The role of peroxidases in the pathogenesis of atherosclerosis,” BMB Reports, vol. 44, no. 8, pp. 497–505, 2011. View at Publisher · View at Google Scholar
  4. D. G. Harrison, M. C. Gongora, T. J. Guzik, and J. Widder, “Oxidative stress and hypertension,” Journal of the American Society of Hypertension, vol. 1, no. 1, pp. 30–44, 2007. View at Publisher · View at Google Scholar · View at Scopus
  5. D. B. Sawyer, “Oxidative stress in heart failure: what are we missing?” The American Journal of the Medical Sciences, vol. 342, no. 2, pp. 120–124, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. J. L. Zweier, P. Kuppusamy, and G. A. Lutty, “Measurement of endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissues,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 11, pp. 4046–4050, 1988. View at Google Scholar · View at Scopus
  7. J. L. Zweier, “Measurement of superoxide-derived free radicals in the reperfused heart. Evidence for a free radical mechanism of reperfusion injury,” The Journal of Biological Chemistry, vol. 263, no. 3, pp. 1353–1357, 1988. View at Google Scholar · View at Scopus
  8. I. Afanas'ev, “ROS and RNS signaling in heart disorders: could antioxidant treatment be successful?” Oxidative Medicine and Cellular Longevity, vol. 2011, Article ID 293769, 13 pages, 2011. View at Publisher · View at Google Scholar
  9. O. Sorg, “Oxidative stress: a theoretical model or a biological reality?” Comptes Rendus, vol. 327, no. 7, pp. 649–662, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. M. M. Berger, “Can oxidative damage be treated nutritionally?” Clinical Nutrition, vol. 24, no. 2, pp. 172–183, 2005. View at Publisher · View at Google Scholar · View at Scopus
  11. I. M. Fearon and S. P. Faux, “Oxidative stress and cardiovascular disease: novel tools give (free) radical insight,” Journal of Molecular and Cellular Cardiology, vol. 47, no. 3, pp. 372–381, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. Y. M. W. Janssen, B. Van Houten, P. J. A. Borm, and B. T. Mossman, “Cell and tissue responses to oxidative damage,” Laboratory Investigation, vol. 69, no. 3, pp. 261–274, 1993. View at Google Scholar · View at Scopus
  13. B. M. Hybertson, B. Gao, S. K. Bose, and J. M. McCord, “Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation,” Molecular Aspects of Medicine, vol. 32, no. 4–6, pp. 234–246, 2011. View at Publisher · View at Google Scholar
  14. N. R. Madamanchi, A. Vendrov, and M. S. Runge, “Oxidative stress and vascular disease,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 1, pp. 29–38, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. R. Ross, “Atherosclerosis—an inflammatory disease,” The New England Journal of Medicine, vol. 340, no. 2, pp. 115–126, 1999. View at Publisher · View at Google Scholar · View at Scopus
  16. T. Asakura and T. Karino, “Flow patterns and spatial distributions of atherosclerotic lesions in human coronary arteries,” Circulation Research, vol. 66, no. 4, pp. 1045–1066, 1990. View at Google Scholar · View at Scopus
  17. C. M. Gibson, L. Diaz, K. Kandarpa et al., “Relation of vessel wall shear stress to atherosclerosis progression in human coronary arteries,” Arteriosclerosis and Thrombosis, vol. 13, no. 2, pp. 310–315, 1993. View at Google Scholar · View at Scopus
  18. D. N. Ku, D. P. Giddens, C. K. Zarins, and S. Glagov, “Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low and oscillating shear stress,” Arteriosclerosis, vol. 5, no. 3, pp. 293–302, 1985. View at Google Scholar · View at Scopus
  19. C. Napoli, F. de Nigris, S. Williams-Ignarro, O. Pignalosa, V. Sica, and L. J. Ignarro, “Nitric oxide and atherosclerosis: an update,” Nitric Oxide, vol. 15, no. 4, pp. 265–279, 2006. View at Publisher · View at Google Scholar · View at Scopus
  20. 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 · View at Google Scholar · View at Scopus
  21. T. Hosoya, A. Maruyama, M. I. Kang et al., “Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells,” The Journal of Biological Chemistry, vol. 280, no. 29, pp. 27244–27250, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. P. Nigro, J. I. Abe, and B. C. Berk, “Flow shear stress and atherosclerosis: a matter of site specificity,” Antioxidants & Redox Signaling, vol. 15, no. 5, pp. 1405–1414, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. L. C. Bailey-Downs, M. Mitschelen, D. Sosnowska et al., “Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging,” The Journals of Gerontology A, vol. 67, no. 4, pp. 313–329, 2012. View at Google Scholar
  24. G. Dai, S. Vaughn, Y. Zhang, E. T. Wang, G. Garcia-Cardena, and M. A. Gimbrone, “Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2,” Circulation Research, vol. 101, no. 7, pp. 723–733, 2007. View at Publisher · View at Google Scholar · View at Scopus
  25. T. Hosoya, A. Maruyama, M.-I. Kang et al., “Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells,” The Journal of Biological Chemistry, vol. 280, no. 29, pp. 27244–27250, 2005. View at Publisher · View at Google Scholar · View at Scopus
  26. H.-K. Jyrkkänen, E. Kansanen, M. Inkala et al., “Nrf2 regulates antioxidant gene expression evoked by oxidized phospholipids in endothelial cells and murine arteries in vivo,” Circulation Research, vol. 103, no. 1, pp. e1–e9, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. Z. Ungvari, Z. Bagi, A. Feher et al., “Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2,” American Journal of Physiology, vol. 299, no. 1, pp. H18–H24, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. Z. Ungvari, L. Bailey-Downs, T. Gautam et al., “Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia,” American Journal of Physiology, vol. 300, no. 4, pp. H1133–H1140, 2011. View at Publisher · View at Google Scholar
  29. M. Zakkar, K. Van der Heiden, L. A. Luong et al., “Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 11, pp. 1851–1857, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. H. Zhu, Z. Jia, L. Zhang et al., “Antioxidants and phase 2 enzymes in macrophages: regulation by Nrf2 signaling and protection against oxidative and electrophilic stress,” Experimental Biology and Medicine, vol. 233, no. 4, pp. 463–474, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. A. R. Collins, A. A. Gupte, R. Ji et al., “Myeloid deletion of nuclear factor erythroid 2-related factor 2 increases atherosclerosis and liver injury,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 12, pp. 2839–2846, 2012. View at Publisher · View at Google Scholar
  32. A. K. Ruotsalainen, M. Inkala, M. E. Partanen et al., “The absence of macrophage Nrf2 promotes early atherogenesis,” Cardiovascular Research, 2013. View at Publisher · View at Google Scholar
  33. K. Ishikawa and Y. Maruyama, “Heme oxygenase as an intrinsic defense system in vascular wall: implication against atherogenesis,” Journal of Atherosclerosis and Thrombosis, vol. 8, no. 3, pp. 63–70, 2001. View at Google Scholar · View at Scopus
  34. K. Ishikawa, D. Sugawara, X. P. Wang et al., “Heme oxygenase-1 inhibits atherosclerotic lesion formation in LDL-receptor knockout mice,” Circulation Research, vol. 88, no. 5, pp. 506–512, 2001. View at Publisher · View at Google Scholar · View at Scopus
  35. L. D. Orozco, M. H. Kapturczak, B. Barajas et al., “Heme oxygenase-1 expression in macrophages plays a beneficial role in atherosclerosis,” Circulation Research, vol. 100, no. 12, pp. 1703–1711, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. S. H. Juan, T. S. Lee, K. W. Tseng et al., “Adenovirus-mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apolipoprotein E-deficient mice,” Circulation, vol. 104, no. 13, pp. 1519–1525, 2001. View at Google Scholar · View at Scopus
  37. S. F. Yet, M. D. Layne, X. Liu et al., “Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling,” The FASEB Journal, vol. 17, no. 12, pp. 1759–1761, 2003. View at Google Scholar · View at Scopus
  38. S. H. Zhang, R. L. Reddick, J. A. Piedrahita, and N. Maeda, “Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E,” Science, vol. 258, no. 5081, pp. 468–471, 1992. View at Google Scholar · View at Scopus
  39. A. S. Plump, J. D. Smith, T. Hayek et al., “Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells,” Cell, vol. 71, no. 2, pp. 343–353, 1992. View at Publisher · View at Google Scholar · View at Scopus
  40. H. J. Duckers, M. Boehm, A. L. True et al., “Heme oxygenase-1 protects against vascular constriction and proliferation,” Nature Medicine, vol. 7, no. 6, pp. 693–698, 2001. View at Publisher · View at Google Scholar · View at Scopus
  41. D. A. Tulis, W. Durante, K. J. Peyton, A. J. Evans, and A. I. Schafer, “Heme oxygenase-1 attenuates vascular remodeling following balloon injury in rat carotid arteries,” Atherosclerosis, vol. 155, no. 1, pp. 113–122, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. Z. Han, S. Varadharaj, R. J. Giedt, J. L. Zweier, H. H. Szeto, and B. R. Alevriadou, “Mitochondria-derived reactive oxygen species mediate heme oxygenase-1 expression in sheared endothelial cellss,” The Journal of Pharmacology and Experimental Therapeutics, vol. 329, no. 1, pp. 94–101, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. J. J. Boyle, M. Johns, J. Lo et al., “Heme induces heme oxygenase 1 via Nrf2: role in the homeostatic macrophage response to intraplaque hemorrhage,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 11, pp. 2685–2691, 2011. View at Publisher · View at Google Scholar
  44. P. Libby, Y. Okamoto, V. Z. Rocha, and E. Folco, “Inflammation in atherosclerosis: transition from theory to practice,” Circulation Journal, vol. 74, no. 2, pp. 213–220, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. J. A. Morrison, D. W. Jacobsen, D. L. Sprecher, K. Robinson, P. Khoury, and S. R. Daniels, “Serum glutathione in adolescent males predicts parental coronary heart disease,” Circulation, vol. 100, no. 22, pp. 2244–2247, 1999. View at Google Scholar · View at Scopus
  46. B. Buijsse, D. H. Lee, L. Steffen et al., “Low serum glutathione peroxidase activity is associated with increased cardiovascular mortality in individuals with low HDLc's,” PLoS ONE, vol. 7, no. 6, Article ID e38901, 2012. View at Publisher · View at Google Scholar
  47. A. Singh, T. Rangasamy, R. K. Thimmulappa et al., “Glutathione peroxidase 2, the major cigarette smoke-inducible isoform of GPX in lungs, is regulated by Nrf2,” American Journal of Respiratory Cell and Molecular Biology, vol. 35, no. 6, pp. 639–650, 2006. View at Publisher · View at Google Scholar
  48. Y. Konstantino, T. T. Nguyen, R. Wolk, R. J. Aiello, S. G. Terra, and D. A. Fryburg, “Potential implications of matrix metalloproteinase-9 in assessment and treatment of coronary artery disease,” Biomarkers, vol. 14, no. 2, pp. 118–129, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. P. J. Gough, I. G. Gomez, P. T. Wille, and E. W. Raines, “Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice,” The Journal of Clinical Investigation, vol. 116, no. 1, pp. 59–69, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. M. L. Wu, Y. C. Ho, and S. F. Yet, “A central role of heme oxygenase-1 in cardiovascular protection,” Antioxidants & Redox Signaling, vol. 15, no. 7, pp. 1835–1846, 2011. View at Publisher · View at Google Scholar
  51. M. Zakkar, K. Van der Heiden, L. A. Luong et al., “Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 11, pp. 1851–1857, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. R. K. Thimmulappa, K. H. Mai, S. Srisuma, T. W. Kensler, M. Yamamoto, and S. Biswal, “Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray,” Cancer Research, vol. 62, no. 18, pp. 5196–5203, 2002. View at Google Scholar · View at Scopus
  53. R. Hu, C. Xu, G. Shen et al., “Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice,” Cancer Letters, vol. 243, no. 2, pp. 170–192, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. M. A. Riedl, A. Saxon, and D. Diaz-Sanchez, “Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway,” Clinical Immunology, vol. 130, no. 3, pp. 244–251, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. H. Y. Cho, F. Imani, L. Miller-DeGraff et al., “Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease,” American Journal of Respiratory and Critical Care Medicine, vol. 179, no. 2, pp. 138–150, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. T. E. Sussan, J. Jun, R. Thimmulappa et al., “Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice,” PLoS ONE, vol. 3, no. 11, Article ID e3791, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. B. Barajas, N. Che, F. Yin et al., “NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 1, pp. 58–66, 2011. View at Publisher · View at Google Scholar · View at Scopus
  58. J. Lynch, G. A. Kaplan, R. Salonen, and J. T. Salonen, “Socioeconomic status and progression of carotid atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 17, no. 3, pp. 513–519, 1997. View at Google Scholar · View at Scopus
  59. T. Ishii, K. Itoh, E. Ruiz et al., “Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal,” Circulation Research, vol. 94, no. 5, pp. 609–616, 2004. View at Publisher · View at Google Scholar · View at Scopus
  60. K. Ishikawa, D. Sugawara, J. Goto et al., “Heme oxygenase-1 inhibits atherogenesis in Watanabe heritable hyperlipidemic rabbits,” Circulation, vol. 104, no. 15, pp. 1831–1836, 2001. View at Google Scholar · View at Scopus
  61. F. L. Celletti, J. M. Waugh, P. G. Amabile, A. Brendolan, P. R. Hilfiker, and M. D. Dake, “Vascular endothelial growth factor enhances atherosclerotic plaque progression,” Nature Medicine, vol. 7, no. 4, pp. 425–429, 2001. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Lucerna, A. Zernecke, R. de Nooijer et al., “Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment,” Blood, vol. 109, no. 1, pp. 122–129, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. T. Afonyushkin, O. V. Oskolkova, M. Philippova et al., “Oxidized phospholipids regulate expression of ATF4 and VEGF in endothelial cells via NRF2-dependent mechanism: novel point of convergence between electrophilic and unfolded protein stress pathways,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 5, pp. 1007–1013, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. X. L. Chen, S. E. Varner, A. S. Rao et al., “Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism,” The Journal of Biological Chemistry, vol. 278, no. 2, pp. 703–711, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. S. J. Chapple, R. C. Siow, and G. E. Mann, “Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging,” The International Journal of Biochemistry & Cell Biology, vol. 44, no. 8, pp. 1315–1320, 2012. View at Publisher · View at Google Scholar
  66. S. Freigang, F. Ampenberger, G. Spohn et al., “Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis,” European Journal of Immunology, vol. 41, no. 7, pp. 2040–2051, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. H. de Groot and U. Rauen, “Ischemia-reperfusion injury: processes in pathogenetic networks: a review,” Transplantation Proceedings, vol. 39, no. 2, pp. 481–484, 2007. View at Publisher · View at Google Scholar · View at Scopus
  68. Z. Cao, H. Zhu, L. Zhang, X. Zhao, J. L. Zweier, and Y. Li, “Antioxidants and phase 2 enzymes in cardiomyocytes: chemical inducibility and chemoprotection against oxidant and simulated ischemia-reperfusion injury,” Experimental Biology and Medicine, vol. 231, no. 8, pp. 1353–1364, 2006. View at Google Scholar · View at Scopus
  69. N. Gurusamy, G. Malik, N. V. Gorbunov, and D. K. Das, “Redox activation of Ref-1 potentiates cell survival following myocardial ischemia reperfusion injury,” Free Radical Biology & Medicine, vol. 43, no. 3, pp. 397–407, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. J. W. Calvert, S. Jha, S. Gundewar et al., “Hydrogen sulfide mediates cardioprotection through Nrf2 signaling,” Circulation Research, vol. 105, no. 4, pp. 365–374, 2009. View at Publisher · View at Google Scholar · View at Scopus
  71. Y. Zhang, M. Sano, K. Shinmura et al., “4-hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway,” Journal of Molecular and Cellular Cardiology, vol. 49, no. 4, pp. 576–586, 2010. View at Publisher · View at Google Scholar · View at Scopus
  72. E. Grossman, “Does increased oxidative stress cause hypertension?” Diabetes care, vol. 31, supplement 2, pp. S185–S189, 2008. View at Google Scholar · View at Scopus
  73. J. de Champlain, R. Wu, H. Girouard et al., “Oxidative stress in hypertension,” Clinical and Experimental Hypertension, vol. 26, no. 7-8, pp. 593–601, 2004. View at Publisher · View at Google Scholar · View at Scopus
  74. C. Delles, W. H. Miller, and A. F. Dominiczak, “Targeting reactive oxygen species in hypertension,” Antioxidants & Redox Signaling, vol. 10, no. 6, pp. 1061–1077, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. P. K. Mehta and K. K. Griendling, “Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system,” American Journal of Physiology, vol. 292, no. 1, pp. C82–C97, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. R. P. Brandes, N. Weissmann, and K. Schröder, “NADPH oxidases in cardiovascular disease,” Free Radical Biology & Medicine, vol. 49, no. 5, pp. 687–706, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. O. Jung, J. G. Schreiber, H. Geiger, T. Pedrazzini, R. Busse, and R. P. Brandes, “gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension,” Circulation, vol. 109, no. 14, pp. 1795–1801, 2004. View at Publisher · View at Google Scholar · View at Scopus
  78. K. Matsuno, H. Yamada, K. Iwata et al., “Nox1 is involved in angiotensin II-mediated hypertension,” Circulation, vol. 112, no. 17, pp. 2677–2685, 2005. View at Publisher · View at Google Scholar · View at Scopus
  79. V. Malec, O. R. Gottschald, S. Li, F. Rose, W. Seeger, and J. Hänze, “HIF-1α signaling is augmented during intermittent hypoxia by induction of the Nrf2 pathway in NOX1-expressing adenocarcinoma A549 cells,” Free Radical Biology & Medicine, vol. 48, no. 12, pp. 1626–1635, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. C. E. Murdoch, S. P. Alom-Ruiz, M. Wang et al., “Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction,” Basic Research in Cardiology, vol. 106, no. 4, pp. 527–538, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. T. M. Chen, J. Li, L. Liu et al., “Effects of heme oxygenase-1 upregulation on blood pressure and cardiac function in an animal model of hypertensive myocardial infarction,” International Journal of Molecular Sciences, vol. 14, no. 2, pp. 2684–2706, 2013. View at Publisher · View at Google Scholar
  82. D. Sacerdoti, B. Escalante, N. G. Abraham, J. C. McGiff, R. D. Levere, and M. L. Schwartzman, “Treatment with tin prevents the development of hypertension in spontaneously hypertensive rats,” Science, vol. 243, no. 4889, pp. 388–390, 1989. View at Google Scholar · View at Scopus
  83. B. Escalante, D. Sacerdoti, M. M. Davidian, M. Laniado-Schwartzman, and J. C. McGiff, “Chronic treatment with tin normalizes blood pressure in spontaneously hypertensive rats,” Hypertension, vol. 17, no. 6, part 1, pp. 776–779, 1991. View at Google Scholar · View at Scopus
  84. S. W. Ryter, L. E. Otterbein, D. Morse, and A. M. K. Choi, “Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance,” Molecular and Cellular Biochemistry, vol. 234-235, no. 1-2, pp. 249–263, 2002. View at Publisher · View at Google Scholar · View at Scopus
  85. D. Sacerdoti, D. Mania, P. Pesce, S. Gaiani, A. Gatta, and M. Bolognesi, “Role of HO/CO in the control of peripheral circulation in humans,” International Journal of Hypertension, vol. 2012, Article ID 236180, 4 pages, 2012. View at Publisher · View at Google Scholar
  86. T. Morita and S. Kourembanas, “Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide,” The Journal of Clinical Investigation, vol. 96, no. 6, pp. 2676–2682, 1995. View at Google Scholar · View at Scopus
  87. J. F. Ndisang, W. Zhao, and R. Wang, “Selective regulation of blood pressure by heme oxygenase-1 in hypertension,” Hypertension, vol. 40, no. 3, pp. 315–321, 2002. View at Publisher · View at Google Scholar · View at Scopus
  88. R. D. Levere, P. Martasek, B. Escalante, M. L. Schwartzman, and N. G. Abraham, “Effect of heme arginate administration on blood pressure in spontaneously hypertensive rats,” The Journal of Clinical Investigation, vol. 86, no. 1, pp. 213–219, 1990. View at Google Scholar · View at Scopus
  89. P. Martasek, M. L. Schwartzman, A. I. Goodman, K. B. Solangi, R. D. Levere, and N. G. Abraham, “Hemin and L-arginine regulation of blood pressure in spontaneous hypertensive rats,” Journal of the American Society of Nephrology, vol. 2, no. 6, pp. 1078–1084, 1991. View at Google Scholar · View at Scopus
  90. Y. H. Chen, S. F. Yet, and M. A. Perrella, “Role of heme oxygenase-1 in the regulation of blood pressure and cardiac function,” Experimental Biology and Medicine, vol. 228, no. 5, pp. 447–453, 2003. View at Google Scholar · View at Scopus
  91. J. Li, C. Zhang, Y. Xing et al., “Up-regulation of p27kip1 contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy,” Cardiovascular Research, vol. 90, no. 2, pp. 315–324, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. M. Gomez-Guzman, R. Jimenez, M. Sanchez et al., “Epicatechin lowers blood pressure, restores endothelial function, and decreases oxidative stress and endothelin-1 and NADPH oxidase activity in DOCA-salt hypertension,” Free Radical Biology & Medicine, vol. 52, no. 1, pp. 70–79, 2012. View at Publisher · View at Google Scholar
  93. R. Bolli, W. X Zhu, C. J. Hartley et al., “Attenuation of dysfunction in the postischemic ‘stunned’ myocardium by dimethylthiourea,” Circulation, vol. 76, no. 2, pp. 458–468, 1987. View at Google Scholar · View at Scopus
  94. A. Beresewicz and M. Horackova, “Alterations in electrical and contractile behavior of isolated cardiomyocytes by hydrogen peroxide: possible ionic mechanisms,” Journal of Molecular and Cellular Cardiology, vol. 23, no. 8, pp. 899–918, 1991. View at Publisher · View at Google Scholar · View at Scopus
  95. A. Chesley, M. S. Lundberg, T. Asai et al., “The β2-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through G(i)-dependent coupling to phosphatidylinositol 3-kinase,” Circulation Research, vol. 87, no. 12, pp. 1172–1179, 2000. View at Google Scholar · View at Scopus
  96. P. Wiesel, A. P. Patel, I. M. Carvajal et al., “Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1—deficient mice,” Circulation Research, vol. 88, no. 10, pp. 1088–1094, 2001. View at Google Scholar · View at Scopus
  97. C.-M. Hu, Y.-H. Chen, M.-T. Chiang, and L.-Y. Chau, “Heme oxygenase-1 inhibits angiotensin II-induced cardiac hypertrophy in vitro and in vivo,” Circulation, vol. 110, no. 3, pp. 309–316, 2004. View at Publisher · View at Google Scholar · View at Scopus
  98. Z. Lu, X. Xu, X. Hu et al., “Extracellular superoxide dismutase deficiency exacerbates pressure overload-induced left ventricular hypertrophy and dysfunction,” Hypertension, vol. 51, no. 1, pp. 19–25, 2008. View at Publisher · View at Google Scholar · View at Scopus
  99. S. Matsushima, S. Kinugawa, T. Ide et al., “Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart,” American Journal of Physiology, vol. 291, no. 5, pp. H2237–H2245, 2006. View at Publisher · View at Google Scholar · View at Scopus
  100. J. Li, T. Ichikawa, L. Villacorta et al., “Nrf2 protects against maladaptive cardiac responses to hemodynamic stress,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 11, pp. 1843–1850, 2009. View at Publisher · View at Google Scholar · View at Scopus
  101. A. C. Brewer, T. V. A. Murray, M. Arno et al., “Nox4 regulates Nrf2 and glutathione redox in cardiomyocytes in vivo,” Free Radical Biology & Medicine, vol. 51, no. 1, pp. 205–215, 2011. View at Publisher · View at Google Scholar · View at Scopus
  102. J. Kuroda, T. Ago, S. Matsushima, P. Zhai, M. D. Schneider, and J. Sadoshima, “NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 35, pp. 15565–15570, 2010. View at Publisher · View at Google Scholar · View at Scopus
  103. H. Ashrafian, G. Czibik, M. Bellahcene et al., “Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway,” Cell Metabolism, vol. 15, no. 3, pp. 361–371, 2012. View at Publisher · View at Google Scholar
  104. T. Ichikawa, J. Li, C. J. Meyer, J. S. Janicki, M. Hannink, and T. Cui, “Dihydro-CDDO-trifluoroethyl amide (dh404), a novel Nrf2 activator, suppresses oxidative stress in cardiomyocytes,” PLoS ONE, vol. 4, no. 12, p. e8391, 2009. View at Google Scholar · View at Scopus
  105. Y. Xing, T. Niu, W. Wang et al., “Triterpenoid dihydro-CDDO-trifluoroethyl amide protects against maladaptive cardiac remodeling and dysfunction in mice: a critical role of Nrf2,” PLoS ONE, vol. 7, no. 9, Article ID e44899, 2012. View at Publisher · View at Google Scholar
  106. T. E. Sussan, T. Rangasamy, D. J. Blake et al., “Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 1, pp. 250–255, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. H. Motohashi and M. Yamamoto, “Nrf2-Keap1 defines a physiologically important stress response mechanism,” Trends in Molecular Medicine, vol. 10, no. 11, pp. 549–557, 2004. View at Publisher · View at Google Scholar · View at Scopus
  108. N. S. Rajasekaran, P. Connell, E. S. Christians et al., “Human αB-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice,” Cell, vol. 130, no. 3, pp. 427–439, 2007. View at Publisher · View at Google Scholar · View at Scopus
  109. N. S. Rajasekaran, S. Varadharaj, G. D. Khanderao et al., “Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice,” Antioxidants & Redox Signaling, vol. 14, no. 6, pp. 957–971, 2011. View at Publisher · View at Google Scholar · View at Scopus
  110. Y. Tan, T. Ichikawa, J. Li et al., “Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo,” Diabetes, vol. 60, no. 2, pp. 625–633, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. S. Papaiahgari, S. R. Kleeberger, H. Y. Cho, D. V. Kalvakolanu, and S. P. Reddy, “NADPH oxidase and ERK signaling regulates hyperoxia-induced Nrf2-ARE transcriptional response in pulmonary epithelial cells,” The Journal of Biological Chemistry, vol. 279, no. 40, pp. 42302–42312, 2004. View at Publisher · View at Google Scholar · View at Scopus
  112. K. Z. Guyton, M. Gorospe, T. W. Kensler, and N. J. Holbrook, “Mitogen-activated protein kinase (MAPK) activation by butylated hydroxytoluene hydroperoxide: implications for cellular survival and tumor promotion,” Cancer Research, vol. 56, no. 15, pp. 3480–3485, 1996. View at Google Scholar · View at Scopus
  113. K. Z. Guyton, Y. Liu, M. Gorospe, Q. Xu, and N. J. Holbrook, “Activation of mitogen-activated protein kinase by H2O2: role in cell survival following oxidant injury,” The Journal of Biological Chemistry, vol. 271, no. 8, pp. 4138–4142, 1996. View at Google Scholar · View at Scopus
  114. R. Aikawa, I. Komuro, T. Yamazaki et al., “Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats,” The Journal of Clinical Investigation, vol. 100, no. 7, pp. 1813–1821, 1997. View at Google Scholar · View at Scopus
  115. X. Wang, J. L. Martindale, Y. Liu, and N. J. Holbrook, “The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival,” Biochemical Journal, vol. 333, part 2, pp. 291–300, 1998. View at Google Scholar · View at Scopus
  116. D. Peus and M. R. Pittelkow, “Reactive oxygen species as mediators of UVB-induced mitogen-activated protein kinase activation in keratinocytes,” Current Problems in Dermatology, vol. 29, pp. 114–127, 2001. View at Google Scholar · View at Scopus
  117. S. Ikeyama, G. Kokkonen, S. Shack, X. T. Wang, and N. J. Holbrook, “Loss in oxidative stress tolerance with aging linked to reduced extracellular signal-regulated kinase and Akt kinase activities,” The FASEB Journal, vol. 16, no. 1, pp. 114–116, 2002. View at Google Scholar · View at Scopus
  118. I. Petrache, M. E. Choi, L. E. Otterbein et al., “Mitogen-activated protein kinase pathway mediates hyperoxia-induced apoptosis in cultured macrophage cells,” American Journal of Physiology, vol. 277, no. 3, pp. L589–L595, 1999. View at Google Scholar · View at Scopus
  119. X. Zhang, P. Shan, M. Sasidhar et al., “Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia-induced cell death in lung epithelium,” American Journal of Respiratory Cell and Molecular Biology, vol. 28, no. 3, pp. 305–315, 2003. View at Publisher · View at Google Scholar · View at Scopus
  120. L. O. Murphy and J. Blenis, “MAPK signal specificity: the right place at the right time,” Trends in Biochemical Sciences, vol. 31, no. 5, pp. 268–275, 2006. View at Publisher · View at Google Scholar · View at Scopus
  121. S. Cagnol and J. C. Chambard, “ERK and cell death: mechanisms of ERK-induced cell death—apoptosis, autophagy and senescence,” FEBS Journal, vol. 277, no. 1, pp. 2–21, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. V. R. Muthusamy, S. Kannan, K. Sadhaasivam et al., “Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium,” Free Radical Biology & Medicine, vol. 52, no. 2, pp. 366–376, 2012. View at Publisher · View at Google Scholar
  123. J. H. Suh, S. V. Shenvi, B. M. Dixon et al., “Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 10, pp. 3381–3386, 2004. View at Publisher · View at Google Scholar · View at Scopus
  124. Z. Ungvari, L. Bailey-Downs, T. Gautam et al., “Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta,” The Journals of Gerontology A, vol. 66, no. 8, pp. 866–875, 2011. View at Google Scholar
  125. Z. Ungvari, L. Bailey-Downs, D. Sosnowska et al., “Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response,” American Journal of Physiology, vol. 301, no. 2, pp. H363–H372, 2011. View at Publisher · View at Google Scholar · View at Scopus
  126. R. J. Goldberg, J. M. Gore, and J. H. Gurwitz, “Coronary thrombolysis for the elderly?” The Journal of the American Medical Association, vol. 265, no. 13, pp. 1720–1723, 1991. View at Publisher · View at Google Scholar · View at Scopus
  127. S. S. Gounder, S. Kannan, D. Devadoss et al., “Impaired transcriptional activity of Nrf2 in age-related myocardial oxidative stress is reversible by moderate exercise training,” PLoS ONE, vol. 7, no. 9, Article ID e45697, 2012. View at Google Scholar
  128. H. Y. Cho, A. E. Jedlicka, S. P. M. Reddy, L. Y. Zhang, T. W. Kensler, and S. R. Kleeberger, “Linkage analysis of susceptibility to hyperoxia Nrf2 is a candidate gene,” American Journal of Respiratory Cell and Molecular Biology, vol. 26, no. 1, pp. 42–51, 2002. View at Google Scholar · View at Scopus
  129. D. E. Schraufnagel, J. L. Basterra, K. Hainis, and J. I. Sznajder, “Lung lymphatics increase after hyperoxic injury: an ultrastructural study of casts,” The American Journal of Pathology, vol. 144, no. 6, pp. 1393–1402, 1994. View at Google Scholar · View at Scopus
  130. D. A. Parrish, B. C. Mitchell, P. M. Henson, and G. L. Larsen, “Pulmonary response of fifth component of complement-sufficient and -deficient mice to hyperoxia,” The Journal of Clinical Investigation, vol. 74, no. 3, pp. 956–965, 1984. View at Google Scholar · View at Scopus
  131. R. Jones, W. M. Zapol, and L. Reid, “Oxygen toxicity and restructuring of pulmonary arteries—a morphometric study. The response to 4 weeks' exposure to hyperoxia and return to breathing air,” The American Journal of Pathology, vol. 121, no. 2, pp. 212–223, 1985. View at Google Scholar · View at Scopus
  132. C. J. Johnston, G. W. Mango, J. N. Finkelstein, and B. R. Stripp, “Altered pulmonary response to hyperoxia in clara cell secretory protein deficient mice,” American Journal of Respiratory Cell and Molecular Biology, vol. 17, no. 2, pp. 147–155, 1997. View at Google Scholar · View at Scopus
  133. N. C. Margaretten and H. Witschi, “Effects of hyperoxia on growth characteristics of metastatic murine tumors in the lung,” Cancer Research, vol. 48, no. 10, pp. 2779–2783, 1988. View at Google Scholar · View at Scopus
  134. M. A. O'Reilly, R. J. Staversky, B. R. Stripp, and J. N. Finkelstein, “Exposure to hyperoxia induces p53 expression in mouse lung epithelium,” American Journal of Respiratory Cell and Molecular Biology, vol. 18, no. 1, pp. 43–50, 1998. View at Google Scholar · View at Scopus
  135. J. D. Crapo, “Morphologic changes in pulmonary oxygen toxicity,” Annual Review of Physiology, vol. 48, pp. 721–731, 1986. View at Google Scholar · View at Scopus
  136. R. Howden, H. Y. Cho, L. Miller-DeGraff et al., “Cardiac physiologic and genetic predictors of hyperoxia-induced acute lung injury in mice,” American Journal of Respiratory Cell and Molecular Biology, vol. 46, no. 4, pp. 470–478, 2012. View at Publisher · View at Google Scholar
  137. R. Howden, E. Liu, L. Miller-DeGraff et al., “The genetic contribution to heart rate and heart rate variability in quiescent mice,” American Journal of Physiology, vol. 295, no. 1, pp. H59–H68, 2008. View at Publisher · View at Google Scholar · View at Scopus
  138. A. K. Parekh and M. B. Barton, “The challenge of multiple comorbidity for the US health care system,” The Journal of the American Medical Association, vol. 303, no. 13, pp. 1303–1304, 2010. View at Publisher · View at Google Scholar · View at Scopus