Therapeutic Effects of PPAR<b><i>α</i></b> on Neuronal Death and Microvascular Impairment

Moran, Elizabeth P.; Ma, Jian-xing

doi:https://doi.org/10.1155/2015/595426

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Volume 2015 | Article ID 595426 | https://doi.org/10.1155/2015/595426

Therapeutic Effects of PPARα on Neuronal Death and Microvascular Impairment

Elizabeth P. Moran¹and Jian-xing Ma^1,2,3,4

Academic Editor: Paul D. Drew

Received06 Nov 2014

Revised09 Jan 2015

Accepted09 Jan 2015

Published29 Jan 2015

Abstract

Peroxisome-proliferator activated receptor-alpha (PPARα) is a broadly expressed nuclear hormone receptor and is a transcription factor for diverse target genes possessing a PPAR response element (PPRE) in the promoter region. The PPRE is highly conserved, and PPARs thus regulate transcription of an extensive array of target genes involved in energy metabolism, vascular function, oxidative stress, inflammation, and many other biological processes. PPARα has potent protective effects against neuronal cell death and microvascular impairment, which have been attributed in part to its antioxidant and anti-inflammatory properties. Here we discuss PPARα’s effects in neurodegenerative and microvascular diseases and also recent clinical findings that identified therapeutic effects of a PPARα agonist in diabetic microvascular complications.

1. Introduction

1.1. Peroxisome-Proliferator Activated Receptor-Alpha (PPARα)

PPARα is a transcription factor and belongs to the nuclear receptor superfamily [1]. PPARα is activated when bound by endogenous lipid/lipid metabolite ligands or synthetic xenobiotic ligands [2]. Once activated, PPARα heterodimerizes with the Retinoid X Receptor (RXR) and binds to PPAR Response Elements (PPREs) in the promoter regions of target genes involved in diverse processes such as energy metabolism, oxidative stress, inflammation, circadian rhythm, immune response, and cell differentiation [3–8]. PPARα has beneficial effects in many diseases but also plays a pathological role in some conditions, for example the development of insulin resistance [3].

PPARα has neuroprotective effects in several disease models including stroke, Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, diabetic peripheral neuropathy, and retinopathy [8–12]. These neuroprotective effects have been attributed largely to PPARα’s antioxidant and anti-inflammatory properties, although its beneficial effects in lipid metabolism and glucose homeostasis may also play a role [7–11].

PPARα also has beneficial effects in the vasculature and plays a more prominent role in the microvasculature than in the macrovasculature. PPARα has protective effects in endothelial dysfunction, hypertension, vasoregression, pathological neovascularization, and vascular hyperpermeability [13–15]. These effects are also modulated by decreased oxidative stress and inflammation and additionally increased endothelial nitric oxide synthase (eNOS) activation, improved endothelial function, and decreased levels of vascular growth factors.

Interestingly, PPARα is downregulated in the diabetic retina and kidney, and although the regulatory mechanisms responsible for diabetes-induced PPARα downregulation are unclear, decreased PPARα levels may play a pathological role in diabetic microvascular complications [15, 16]. Further, our group found that retinal levels of PPARα, but not PPARγ or PPARβ/δ, were decreased in diabetes, suggesting that PPARα plays a more crucial role than other PPARs in repressing development of diabetic retinopathy (DR) [15].

Two major clinical trials have evaluated the effects of the PPARα agonist in diabetic complications and identified as tertiary outcomes that fenofibrate significantly decreased diabetic microvascular complications including retinopathy, nephropathy, and peripheral neuropathy in type 2 diabetic patients [17, 18]. These tertiary outcomes were identified by intent to treat analysis, leaving the underlying physiological and molecular mechanisms of action incompletely understood. PPARα has since become a topic of intense investigation in diabetic microvascular complications [2].

1.2. Neuronal Cell Death

In neuronal cell death, neurons of the central or peripheral nervous systems die due to age-related conditions, traumatic injury, diabetic insults, vascular dysfunction, ischemia, metabolic aberrations, or a combination of these and other factors [40–43]. Although the molecular pathogenesis for neurodegenerative disease is unique to each condition, oxidative stress, inflammation, and microvascular dysfunction play prominent roles in many neurodegenerative diseases, and interventions that correct these parameters have therapeutic effects [40–42].

1.3. Microvascular Impairment

Microvascular aberrations participate in the pathogenesis of myriad diseases, and interventions for these abnormalities have considerable therapeutic potential. Endothelial dysfunction, vascular hyperpermeability, pericyte dropout, vasoregression, and neovascularization play prominent roles in microvascular disease [44–46]. The molecular mechanisms for these abnormalities are complex, but inflammation, oxidative stress, vascular growth factors, dyslipidemia, and tight junction interruption are major contributing factors [44–46]. Further, neurodegeneration may also cause microvascular impairment in some neurovascular diseases, such as DR and ischemic stroke.

2. Protective Effects of PPARα in Neuronal Cell Death

PPARα has neuroprotective effects in many disease models including cerebral ischemia/reperfusion, traumatic brain and spinal cord injury, Parkinson’s disease, Alzheimer’s disease, peripheral neuropathy, ischemic retinopathy, and DR (Table 1). PPARα’s neuroprotective capacity has been largely attributed to its antioxidant and anti-inflammatory effects, which may decrease neuronal cell death in these models [9, 28]. However, PPARα’s beneficial effects in endothelial survival and function may also play a role in PPARα-mediated neuroprotection, as vascular dysfunction contributes to many neurodegenerative diseases [47, 48].

The molecular basis of neuronal cell death is complex and may be context dependent. However, oxidative stress and inflammation play prominent roles in many neurodegenerative diseases, and experimental evidence suggests that PPARα’s antioxidant and anti-inflammatory properties may be responsible in part for its neuroprotective effects.

Although physiological reactive oxygen species (ROS) levels play critical roles in cellular signaling and physiology [49], an overabundance of ROS may be detrimental. ROS are highly unstable intermediates, and oxidize cellular macromolecules such as phospholipids, proteins, and DNA [50]. This oxidative damage, or oxidative stress, leads to cellular death and dysfunction, including neurodegeneration [50]. Oxidative stress also increases inflammation, glial activation, and mitochondrial dysfunction, further exacerbating neurodegeneration. Neurons are acutely sensitive to ROS, and oxidative stress contributes to neurodegeneration in many disease models.

Neuronal inflammation, or neuroinflammation, plays a significant role in neurodegenerative disease. Inflammation in neuronal cells directly activates apoptotic pathways through mitogen activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling [51]. Neuroinflammation also results in endothelial cell (EC) loss, blood-brain barrier breakdown, and glial activation, further exacerbating neurodegeneration.

2.1. Cerebral Ischemia

Deplanque et al. first demonstrated that PPARα is neuroprotective in cerebral ischemia [9]. The authors subjected wild-type and apolipoprotein E-deficient (ApoE^−/−) mice to middle cerebral artery occlusion and identified that the PPARα agonist fenofibrate decreased the susceptibility of ApoE^−/− mice to stroke and also decreased infarct volume in wild-type animals [9]. These effects were abrogated by PPARα ablation, indicating that fenofibrate’s neuroprotective effects in this model were PPARα-dependent [9]. The same study identified that fenofibrate significantly increased the activities of antioxidant enzymes superoxide dismutase and catalase in cerebral ischemia, which deactivate ROS to alleviate oxidative stress [9]. Further, PPARα decreased expression of vascular adhesion molecules, subsequently lessening inflammation and improving vasoreactivity in animals subjected to middle cerebral artery occlusion [9]. The authors thus concluded that PPARα’s neuroprotective effects in cerebral ischemia were due to alleviation of ischemia-induced oxidative stress and inflammation and improved cerebral microvascular function [9].

Ouk et al. also identified that fenofibrate had a neuroprotective effect in ischemic brain injury by subjecting rats and mice to midcerebral artery occlusion and measuring infarct volume, motor and cognitive function, vascular function, and neurogenesis [19]. Fenofibrate improved neuronal function and decreased infarct volume in acute cerebral ischemia and also improved vascular response [19]. Additionally, fenofibrate modulated neurorepair and inhibited the amyloid cascade, suggesting that it may have protective effects in other traumatic brain injury models and chronic neurodegenerative diseases [19].

Other studies have also demonstrated that PPARα improves outcomes of cerebral ischemia and that its protective effects may be due to its antioxidant and anti-inflammatory properties and beneficial effects in vascular function, which may be through similar molecular mechanisms to those described above [20, 52].

2.2. Traumatic Brain and Spinal Cord Injury

PPARα has neuroprotective effects in traumatic brain and spinal cord injury, which are modulated by its anti-inflammatory and antioxidant effects [21, 22]. Genovese et al. subjected wild-type and PPARα knockout (PPARα^−/−) mice to spinal cord compression injury and observed that spinal cord trauma, neutrophil infiltration, oxidative stress, and neuronal apoptosis were significantly increased in PPARα^−/− mice in comparison to wild-type mice [21]. Further, Besson et al. subjected rats to traumatic brain injury and demonstrated that fenofibrate improved neurological deficit, brain lesions, and cerebral oedema and decreased intracellular adhesion molecule-1 (ICAM-1) expression, suggesting neuroprotective and anti-inflammatory effects, although the precise molecular mechanisms of action were not defined [22]. Other studies have also suggested that PPARα agonists have neuroprotective effects in similar models [23–25].

2.3. Alzheimer’s Disease

Clinical and basic research findings have suggested that PPARα may have a therapeutic effect in Alzheimer’s disease, but these findings remain controversial. van Rossum and Hanisch identified that PPARα agonists inhibited beta-amyloid stimulated proinflammatory responses in vitro, and Santos et al. demonstrated that PPARα had a protective effect against beta-amyloid-induced neurodegeneration [52, 53]. However, Kukar et al. found that fenofibrate increased beta-amyloid production in vitro, although this interaction was not demonstrated to be PPARα-dependent, so it may be an off-target effect [54]. A genetic epidemiological study suggested that PPARα single nucleotide polymorphisms (SNPs) were associated with increased Alzheimer’s disease risk, although later studies contradicted this finding [55, 56].

2.4. Parkinson’s Disease

Recent Studies have demonstrated that PPARα holds potential as a therapeutic target for Parkinson’s disease, which is a chronic neurodegenerative disorder of the central nervous system characterized by loss of dopaminergic neurons [57].

Fenofibrate and PPARα had neuroprotective effects in a toxin-induced model of Parkinson’s disease, and these effects were mediated in part by decreased oxidative stress [8, 26]. Barbiero et al. also demonstrated that PPARα and PPARγ agonists had protective effects in a similar animal model of Parkinson’s disease, preserving locomotor and cognitive activity and preventing loss and dysfunction of dopaminergic neurons [58].

Uppalapati et al. corroborated that fenofibrate was neuroprotective in Parkinson’s disease and suggested that this effect was due to decreased inflammation in the brains of fenofibrate-treated animals [27]. Importantly, this study also used pharmacokinetic analysis to demonstrate that fenofibric acid, the bioactive metabolite of fenofibrate, was present in the brains of fenofibrate-treated animals, suggesting that fenofibrate was metabolized and successfully crossed the blood-brain barrier in vivo [27].

Although the mechanism(s) of action for PPARα-mediated neuroprotection in Parkinson’s disease have not been fully defined, Barbiero et al. found that fenofibrate-treated animals had decreased levels of oxidative stress biomarkers, suggesting an antioxidant effect [8, 58]. Further, Uppalapati et al. found that fenofibrate decreased brain levels of proinflammatory mediators, suggesting that PPARα also has anti-inflammatory effects in this model [27].

2.5. Peripheral Neuropathy

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) clinical trial identified that fenofibrate significantly decreased diabetic peripheral neuropathy (DPN) in human patients, as demonstrated by decreased nontraumatic limb amputation and improved sensory threshold in patients receiving fenofibrate treatment [11, 29]. Cho et al. have since revealed that fenofibrate has a therapeutic effect in DPN in a mouse model of type 2 diabetes and may modulate this effect in part by improving endothelial and neuronal survival through AMP-activated protein kinase (AMPK)/phosphoinositide-3 kinase (PI3K) activation [28]. Although the downstream antiapoptotic mechanisms for PI3K are not evaluated in the experimental model, the authors propose that inhibition of MAPK signaling and caspase activity together with increased expression of the antiapoptotic proteins survivin and Bcl-2 may be responsible for fenofibrate’s cytoprotective effects in DPN [28].

Basic research findings have also demonstrated that PPARα has a protective role in neuropathic pain, although the mechanisms for these effects are not fully understood. Ruiz-Medina et al. demonstrated that PPARα^−/− mice were more susceptible to visceral and acute thermal nociception and had higher levels of proinflammatory factors in sciatic nerve injury [59]. Additionally, PPARα agonists have analgesic effects in visceral, inflammatory, and neuropathic pain [60–62].

2.6. Retinopathy

Because PPARα has a therapeutic effect in DR and is neuroprotective in several disease models, it is reasonable to hypothesize that PPARα may be neuroprotective in retinopathy, which is characterized in part by neurodegeneration [4, 63, 64]. We and others have demonstrated that PPARα has neuroprotective effects in retinopathy and that this protective effect may be due to alleviation of oxidative stress and inflammation [12, 30].

Our group first demonstrated that activation and expression of PPARα had a neuroprotective effect in oxygen-induced retinopathy (OIR), a model of ischemic retinopathy [12]. In contrast, PPARα ablation exacerbated ischemia-induced neuron death. In OIR, PPARα repressed activation of hypoxia-inducible factor-1-alpha (HIF-1α) and subsequently decreased HIF-1α-driven transcription of NADPH oxidase-4 (Nox4), which produces ROS by catalyzing electron transport from NADPH to molecular oxygen [12, 65]. Further, PPARα inhibited hypoxic ROS production in vitro, and we suggested that this effect was due to decreased Nox4 levels [12]. We postulate that this antioxidant effect may be responsible in part for PPARα-mediated neuroprotection in retinal ischemia [12].

Similarly, Bogdanov and colleagues identified that fenofibrate had a neuroprotective effect in DR using db/db mice, a model of type 2 diabetes [30]. The authors demonstrated that electroretinogram (ERG) amplitude declined in diabetic mice and was improved by fenofibrate [30]. In the same model, retinal glial activation was increased in DR and partially decreased by fenofibrate [30]. Although this study did not define the molecular mechanisms of action, the authors propose that fenofibrate may confer neuroprotection in DR by alleviating inflammation and/or oxidative stress in the diabetic retina [30].

3. Beneficial Effects of PPARα in Microvascular Impairment

PPARα is well known for its beneficial effects in the microvasculature, and clinical trials have demonstrated that it has potent therapeutic effects in diabetic microvascular complications [17, 18]. Further, decreased PPARα levels in diabetes are thought to contribute to inflammation, vascular damage, and neurodegeneration, and exogenous PPARα agonists may compensate for this effect [15]. PPARα’s beneficial effects are multifaceted, and PPARα downregulation has been found to play important roles in vasoregression, endothelial dysfunction, vascular hyperpermeability, and pathological angiogenesis (Table 2).

3.1. Vasoregression

Vasoregression plays a prominent role in many microvascular diseases, particularly in the central and peripheral nervous systems. In vasoregression, EC and pericyte apoptosis, or dropout, results in tissue nonperfusion, which is particularly detrimental to metabolically demanding and highly sensitive neuronal tissues [66–68]. EC apoptosis plays a role in peripheral neuropathy, stroke, traumatic brain injury, and retinopathy [69–71]. In retinopathy, vasoregression-related ischemia also leads to overcompensatory, sight-threatening pathological neovascularization (NV) characteristic of proliferative retinopathies [72].

Vasoregression is a multifaceted process, but EC/pericyte dropout has been attributed in part to ischemia, oxidative stress, inflammation, and endothelial dysfunction [69]. In addition to EC and pericyte apoptosis, reparative endothelial progenitor cells (EPCs), which replace apoptotic ECs and secrete beneficial growth factors, may be compromised in some disease conditions, such as diabetes, further contributing to vasoregression and vascular dysfunction [73, 74].

Our group demonstrated in type 1 diabetic models that fenofibrate and PPARα had a protective effect against DR-induced EC and pericyte dropout, decreasing acellular capillary formation and pericyte loss in the retinas of diabetic animals [13, 15]. In these models, PPARα alleviated oxidative stress and inflammation by suppressing NF-κB activation and subsequent transcription of Nox4 and inflammatory mediators, thereby decreasing oxidative stress and inflammation, respectively [13, 15]. Cho et al. also demonstrated that PPARα decreased EC loss in peripheral diabetic neuropathy and suggested that this effect was mediated in part through AMPK activation and resultant activation of downstream cytoprotective pathways and improvements in endothelial function and vasorelaxation [28].

Further, Deplanque et al. identified that fenofibrate decreased EC loss in a rodent model of cerebral ischemia and suggested that this effect was due in part to increased activity of antioxidant enzymes superoxide dismutase and catalase, with subsequent alleviation of ischemia-related oxidative stress [9]. These findings were further supported in other rodent models of cerebral ischemia and related disorders [19, 20].

Because EC loss and subsequent vasoregression contribute to neurodegeneration in cerebral ischemia, DR, peripheral neuropathy, and age-related neurodegenerative diseases [75], it is likely that PPARα-mediated vasoprotection contributes to the observed neuroprotective effects in these models.

3.2. Endothelial Dysfunction

Endothelial function is regulated by vasoactive factors that maintain proper vascular wall tone to regulate blood flow and prevent vascular inflammation [76]. Nitric oxide (NO) is a potent vasodilator and is necessary for endothelial function [77]. In diabetes and other pathological conditions, the production and bioavailability of NO are compromised, leading to a persistent state of vasoconstriction, inflammation, and oxidative stress [77, 78]. Endothelial dysfunction plays a prominent role in microvascular disease, limiting blood flow and increasing inflammation and oxidative stress [46, 79].

Clinical studies have demonstrated that in human diabetic patients, fibrates decrease markers of endothelial dysfunction and have beneficial effects in vascular function [31–34, 80–82]. These beneficial effects may be mediated in part by increased activation and production of eNOS, decreased endothelin-1 expression, and deactivation of inflammatory NF-κB signaling, subsequently increasing NO levels and alleviating inflammation to improve endothelial function [14, 83, 84]. We and others have also demonstrated that PPARα has beneficial effects in the diabetic microvasculature, and these effects may be due in part to decreased endothelial dysfunction in diabetic conditions [15, 28, 35].

Endothelial dysfunction also plays a prominent role in neurodegenerative disease [66, 85, 86]. It is therefore likely that PPARα restoration of endothelial dysfunction may be responsible in part for its neuroprotective effects in these diseases.

3.3. Vascular Hyperpermeability

Increased vascular permeability, or vascular hyperpermeability, plays a role in diabetic complications, cerebral ischemia, heart failure, and many other diseases [87–89]. Vascular hyperpermeability is caused by EC dropout, inflammation, increased vascular growth factors, and EC tight junction dysfunction [90, 91]. Increased vascular permeability decreases the efficiency of the vasculature and results in widespread ischemia [46]. Vascular hyperpermeability also increases inflammatory processes such as leukostasis and may allow leukocyte infiltration [46].

Our group has identified that activation and expression of PPARα decreases retinal vascular hyperpermeability in animal models of type 1 diabetes and ischemic retinopathy [15, 35]. We have also demonstrated in previous studies that PPARα protects against pericyte and EC dropout in DR, suggesting that PPARα inhibition of vascular hyperpermeability may be due in part to its protective effects against vasoregression [13].

Mazzon et al. also established that PPARα improves tight junction integrity in an animal model of stress-induced intestinal permeability [37]. The authors identified that in PPARα^−/− animals, intestinal permeability was significantly increased under restraint stress [37]. Further, mislocalization of tight junction proteins was increased in PPARα^−/− mice, suggesting that PPARα modulates small intestinal tight junction integrity.

Further, several studies have also suggested that PPARα attenuates blood-brain barrier disruption in HIV-induced cerebrovascular toxicity and cerebral ischemia [92–94]. In HIV-induced cerebrovascular toxicity, PPARα improves HIV deregulation of tight junction proteins by modulating matrix metalloproteinase and proteasome activities, subsequently alleviating tight junction disruption and vascular hyperpermeability in the model [92]. Although PPARα’s beneficial effects upon the blood-brain barrier in cerebral ischemia are not fully understood [94], PPARα may also improve tight junction integrity in this model through mechanisms similar to that in intestinal permeability and HIV-induced cerebrovascular toxicity.

Vascular hyperpermeability and disruption of the blood-brain barrier also play a role in other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury [95–97]. It is thus possible that PPARα’s identified therapeutic effects in these diseases are due in part to improved blood-brain barrier function, which may be modulated through restoration of tight junction proteins or alleviation of inflammation and/or oxidative stress.

3.4. Neovascularization

Pathological NV plays a central role in many diseases including proliferative retinopathies, tumor angiogenesis, atherosclerosis, and others [98–100]. The physiological and molecular mechanisms for NV are complex but are modulated in part by ischemia, inflammation, oxidative stress, and vascular growth factors [45, 101–103]. PPARα is able to repress pathological angiogenesis in part by decreasing inflammation, oxidative stress, and vascular growth factor levels.

We previously demonstrated that PPARα inhibited NV in an OIR model of ischemic retinopathy [35]. Our findings suggested that PPARα decreased expression of vascular endothelial growth factor (VEGF) and its receptors, potentially by deactivating pathological Wnt signaling in retinopathy [15, 35]. It is also possible that PPARα-mediated neuroprotection and/or vasoprotection may be responsible in part for PPARα’s repression of retinal NV [12, 13, 36].

Additionally, Varet et al. identified that fenofibrate repressed angiogenesis in a nude mouse model and in an in vitro wound healing assay and suggested that PPARα may deactivate Akt signaling to inhibit EC proliferation in these models [38]. Meissner et al. also found that PPARα repressed VEGF receptor 2 (VEGFR2) expression by repressing specificity protein 1 (Sp1) binding to the VEGFR2 promoter in human vascular endothelial cells (HUVECs), thereby decreasing VEGF signaling [39].

EPCs play a protective role in vasoregression, but may also contribute to pathological NV, particularly in proliferative retinopathies. In some disease conditions, EPCs also shift to a proinflammatory phenotype that promotes NV [104]. In pathological NV conditions, EPCs migrate to neovascular areas and incorporate themselves into the neovasculature and also secrete vascular growth factors and inflammatory mediators that further exacerbate NV [104].

Our group identified that PPARα suppressed bone marrow EPC mobilization in OIR, a mouse model of ischemic retinopathy [36]. We demonstrated in this study that PPARα decreased retinal expression of EPC homing factors erythropoietin (Epo) and stromal-derived factor-1 (SDF-1) by suppressing HIF-1α activation, therefore inhibiting bone marrow-derived EPC release and homing to the retina [36]. It is thus feasible that PPARα suppression of pathological EPC release may contribute to antiangiogenic effects identified in previous studies.

4. Clinical Findings

PPARα has been identified as an attractive therapeutic target for diabetic complications, and most clinical studies of PPARα have focused predominantly upon its potential therapeutic effects in diabetic complications. The fibrates, a class of lipid-lowering drugs designed to activate PPARs, are the most commonly used PPAR agonists clinically. Fenofibrate in particular is well tolerated and unlike other fibrates does not compete with statins for hepatic clearance, so is utilized nearly exclusively to treat dyslipidemic diabetic patients [105].

Two large randomized perspective clinical trials have demonstrated that fenofibrate decreases the prevalence of diabetic microvascular complications in human patients [18, 63]. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial first identified that fenofibrate monotherapy had a therapeutic effect in DR, neuropathy, and nephropathy, and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial later demonstrated that fenofibrate in a simvastatin background also had therapeutic effects in diabetic microvascular complications [18, 63].

4.1. FIELD Study

The FIELD study was conducted principally to evaluate fenofibrate’s potential therapeutic effects in type 2 diabetes-associated cardiovascular disease [17]. Nearly 10,000 persons with type 2 diabetes from 50 to 75 years old were treated with either fenofibrate or a placebo for five years, and primary outcomes of coronary heart disease or nonfatal myocardial infarct were evaluated by intent to treat analysis [17]. Total cardiovascular events were analyzed as a secondary outcome, and microvascular complications were a tertiary outcome of the FIELD study [17].

Fenofibrate did not change total coronary events, but modestly decreased total cardiovascular events [17]. It is possible, however, that increased statin use by placebo-allocated patients may have masked fenofibrate’s beneficial effects for this outcome [17]. Conversely, fenofibrate had a dramatic therapeutic effect in microvascular diabetic complications, significantly decreasing the incidence of retinopathy, nephropathy, and neuropathy [11, 17, 63, 106]. Because microvascular complications were a tertiary outcome and were identified by intent to treat analysis, the physiological and molecular mechanisms of action for these therapeutic effects were largely unknown when the FIELD trial findings were published [17, 63].

Interestingly, although fenofibrate’s primary clinical application is dyslipidemia, FIELD participants’ lipid profiles were modestly affected by fenofibrate [17]. Fenofibrate decreased serum triglycerides by approximately 30%, but this beneficial effect did not directly correlate with fenofibrate’s therapeutic effects in microvascular complications [17, 63]. These findings suggest that fenofibrate’s therapeutic effects in diabetic microvascular complications may be due in part to lipid-independent mechanisms, as has been further confirmed by the basic research findings outlined above.

4.2. ACCORD Lipid Study

The ACCORD study was conducted to evaluate the effects of intense glycemic control, hypertensive control, and combination lipid therapy upon cardiovascular disease risk in type 2 diabetes. The ACCORD Lipid trial was unique from the FIELD trial in that patients received fenofibrate in a statin background as opposed to fenofibrate monotherapy.

Similar to the FIELD trial, the ACCORD trial also identified that fenofibrate did not affect total coronary events but did decrease incidence of nonfatal myocardial infarct [64]. Fenofibrate also had a therapeutic effect in diabetic microvascular complications including nephropathy, retinopathy, and nontraumatic limb amputation [18].

Together these studies suggested that PPARα had significant therapeutic potential in diabetic microvascular complications but gave little insight into the physiological and molecular mechanisms responsible for its therapeutic effects. PPARα has since been a topic of intense investigation for diabetic microvascular disease, and several basic research studies have begun to delineate its effects in DR, neuropathy, and nephropathy [13, 15, 28, 35, 107, 108].

5. Conclusions and Future Directions

Both clinical and basic research findings have suggested that PPARα has robust neuroprotective and vascular homeostatic effects. These beneficial effects may be due in part to PPARα’s anti-inflammatory and antioxidant properties and also to restoration of endothelial function and vascular tight junction integrity. PPARα’s abilities to decrease oxidative stress, inflammation, and endothelial dysfunction resulting from a variety of pathophysiological events undoubtedly play significant roles in its therapeutic effects.

However, because PPARα target genes are diverse, it is likely that many other mechanisms contribute to both its beneficial and pathological effects in these and other disease models. Ongoing research efforts seek to broaden these horizons to better understand PPARα’s systemic, whole organism effects.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

This work is supported by National Institutes of Health Grants EY012231, EY018659, EY019309, and GM104934, a Grant from Juvenile Diabetes Research Foundation (JDRF) 2-SRA-2014-147-Q-R, and a Grant from Oklahoma Center for the Advancement of Science & Technology (OCAST).

References

J. Wu, L. Chen, D. Zhang et al., “Peroxisome proliferator-activated receptors and renal diseases,” Frontiers in Bioscience, vol. 14, no. 3, pp. 995–1009, 2009.
View at: Publisher Site | Google Scholar
A. Hiukka, M. Maranghi, N. Matikainen, and M.-R. Taskinen, “PPARα: an emerging therapeutic target in diabetic microvascular damage,” Nature Reviews Endocrinology, vol. 6, no. 8, pp. 454–463, 2010.
View at: Publisher Site | Google Scholar
P. Lefebvre, G. Chinetti, J. C. Fruchart, and B. Staels, “Sorting out the roles of PPARα in energy metabolism and vascular homeostasis,” The Journal of Clinical Investigation, vol. 116, no. 3, pp. 571–580, 2006.
View at: Publisher Site | Google Scholar
R. Bordet, T. Ouk, O. Petrault et al., “PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases,” Biochemical Society Transactions, vol. 34, no. 6, pp. 1341–1346, 2006.
View at: Publisher Site | Google Scholar
L. Chen and G. Yang, “PPARs integrate the mammalian clock and energy metabolism,” PPAR Research, vol. 2014, Article ID 653017, 6 pages, 2014.
View at: Publisher Site | Google Scholar
A. Y. Y. Cheng and L. A. Leiter, “PPAR-alpha: therapeutic role in diabetes-related cardiovascular disease,” Diabetes, Obesity and Metabolism, vol. 10, no. 9, pp. 691–698, 2008.
View at: Publisher Site | Google Scholar
A. Papi, T. Guarnieri, G. Storci et al., “Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells,” Cell Death and Differentiation, vol. 19, no. 7, pp. 1208–1219, 2012.
View at: Publisher Site | Google Scholar
J. K. Barbiero, R. Santiago, F. S. Tonin et al., “PPAR-alpha agonist fenofibrate protects against the damaging effects of MPTP in a rat model of Parkinson's disease,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 53, pp. 35–44, 2014.
View at: Publisher Site | Google Scholar
D. Deplanque, P. Gelé, O. Pétrault et al., “Peroxisome proliferator-activated receptor-α activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment,” The Journal of Neuroscience, vol. 23, no. 15, pp. 6264–6271, 2003.
View at: Google Scholar
C. K. Combs, P. Bates, J. C. Karlo, and G. E. Landreth, “Regulation of beta-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha,” Neurochemistry International, vol. 39, no. 5-6, pp. 449–457, 2001.
View at: Publisher Site | Google Scholar
K. Rajamani, P. G. Colman, L. P. Li et al., “Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial,” The Lancet, vol. 373, no. 9677, pp. 1780–1788, 2009.
View at: Publisher Site | Google Scholar
E. Moran, L. Ding, Z. Wang et al., “Protective and antioxidant effects of PPARalpha in the ischemic retina,” Investigative Ophthalmology & Visual Science, vol. 55, no. 7, pp. 4568–4576, 2014.
View at: Publisher Site | Google Scholar
L. Ding, R. Cheng, Y. Hu et al., “Peroxisome proliferator-activated receptor $α$ protects capillary pericytes in the retina,” The American Journal of Pathology, vol. 184, no. 10, pp. 2709–2720, 2014.
View at: Publisher Site | Google Scholar
L. G. Cervantes-Pérez, M. de La Luz Ibarra-Lara, B. Escalante et al., “Endothelial nitric oxide synthase impairment is restored by clofibrate treatment in an animal model of hypertension,” European Journal of Pharmacology, vol. 685, no. 1–3, pp. 108–115, 2012.
View at: Publisher Site | Google Scholar
Y. Hu, Y. Chen, L. Ding et al., “Pathogenic role of diabetes-induced PPAR-α down-regulation in microvascular dysfunction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 38, pp. 15401–15406, 2013.
View at: Publisher Site | Google Scholar
M.-C. Mong and M.-C. Yin, “Nuclear factor κb-dependent anti-inflammatory effects of s-allyl cysteine and s-propyl cysteine in kidney of diabetic mice,” Journal of Agricultural and Food Chemistry, vol. 60, no. 12, pp. 3158–3165, 2012.
View at: Publisher Site | Google Scholar
A. Keech, R. J. Simes, P. Barter et al., “Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial,” The Lancet, vol. 366, no. 9500, pp. 1849–1861, 2005.
View at: Publisher Site | Google Scholar
F. Ismail-Beigi, T. Craven, M. A. Banerji et al., “Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial,” The Lancet, vol. 376, no. 9739, pp. 419–430, 2010.
View at: Publisher Site | Google Scholar
T. Ouk, S. Gautier, M. Pétrault et al., “Effects of the PPAR-α agonist fenofibrate on acute and short-term consequences of brain ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 34, no. 3, pp. 542–551, 2014.
View at: Publisher Site | Google Scholar
M. Collino, M. Aragno, R. Mastrocola et al., “Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: effects of the PPAR-alpha agonist WY14643,” Free Radical Biology & Medicine, vol. 41, no. 4, pp. 579–589, 2006.
View at: Google Scholar
T. Genovese, E. Mazzon, R. Di Paola et al., “Role of endogenous ligands for the peroxisome proliferators activated receptors alpha in the secondary damage in experimental spinal cord trauma,” Experimental Neurology, vol. 194, no. 1, pp. 267–278, 2005.
View at: Publisher Site | Google Scholar
V. C. Besson, X. R. Chen, M. Plotkine, and C. Marchand-Verrecchia, “Fenofibrate, a peroxisome proliferator-activated receptor α agonist, exerts neuroprotective effects in traumatic brain injury,” Neuroscience Letters, vol. 388, no. 1, pp. 7–12, 2005.
View at: Publisher Site | Google Scholar
X. R. Chen, V. C. Besson, T. Beziaud, M. Plotkine, and C. Marchand-Leroux, “Combination therapy with fenofibrate, a peroxisome proliferator-activated receptor α agonist, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on experimental traumatic brain injury,” Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 3, pp. 966–974, 2008.
View at: Publisher Site | Google Scholar
X. R. Chen, V. C. Besson, B. Palmier, Y. Garcia, M. Plotkine, and C. Marchand-Leroux, “Neurological recovery-promoting, anti-inflammatory, and anti-oxidative effects afforded by fenofibrate, a PPAR alpha agonist, in traumatic brain injury,” Journal of Neurotrauma, vol. 24, no. 7, pp. 1119–1131, 2007.
View at: Publisher Site | Google Scholar
L. Khalaj, S. Chavoshi Nejad, M. Mohammadi et al., “Gemfibrozil pretreatment proved protection against acute restraint stress-induced changes in the male rats' hippocampus,” Brain Research, vol. 1527, pp. 117–130, 2013.
View at: Publisher Site | Google Scholar
E. Esposito, D. Impellizzeri, E. Mazzon, I. Paterniti, and S. Cuzzocrea, “Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson's disease,” PLoS ONE, vol. 7, no. 8, Article ID e41880, 2012.
View at: Publisher Site | Google Scholar
D. Uppalapati, N. R. Das, R. P. Gangwal, M. V. Damre, A. T. Sangamwar, and S. S. Sharma, “Neuroprotective potential of peroxisome proliferator activated receptor-α agonist in cognitive impairment in Parkinson's disease: behavioral, biochemical, and PBPK profile,” PPAR Research, vol. 2014, Article ID 753587, 9 pages, 2014.
View at: Publisher Site | Google Scholar
Y. R. Cho, J. H. Lim, M. Y. Kim et al., “Therapeutic effects of fenofibrate on diabetic peripheral neuropathy by improving endothelial and neural survival in db/db mice,” PLoS ONE, vol. 9, no. 1, Article ID 0083204, 2014.
View at: Publisher Site | Google Scholar
K. Rajamani, M. Donoghoe, L. Li et al., “Abstract 18987: fenofibrate reduces peripheral neuropathy in type 2 diabetes: the fenofibrate intervention and event lowering in diabetes (FIELD) study,” Circulation, vol. 122, no. A1, p. 8997, 2010.
View at: Google Scholar
P. Bogdanov, C. Hernández, L. Corraliza, A. R. Carvalho, and R. Simó, “Effect of fenofibrate on retinal neurodegeneration in an experimental model of type 2 diabetes,” Acta Diabetologica, 2014.
View at: Publisher Site | Google Scholar
G. Desideri, G. Croce, M. Tucci et al., “Effects of bezafibrate and simvastatin on endothelial activation and lipid peroxidation in hypercholesterolemia: evidence of different vascular protection by different lipid-lowering treatments,” The Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 11, pp. 5341–5347, 2003.
View at: Publisher Site | Google Scholar
D. A. Playford, G. F. Watts, J. D. Best, and V. Burke, “Effect of fenofibrate on brachial artery flow-mediated dilatation in type 2 diabetes mellitus,” American Journal of Cardiology, vol. 90, no. 11, pp. 1254–1257, 2002.
View at: Publisher Site | Google Scholar
D. A. Playford, G. F. Watts, K. D. Croft, and V. Burke, “Combined effect of coenzyme Q₁₀ and fenofibrate on forearm microcirculatory function in type 2 diabetes,” Atherosclerosis, vol. 168, no. 1, pp. 169–179, 2003.
View at: Publisher Site | Google Scholar
M. Evans, R. A. Anderson, J. Graham et al., “Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus,” Circulation, vol. 101, no. 15, pp. 1773–1779, 2000.
View at: Publisher Site | Google Scholar
Y. Chen, Y. Hu, M. Lin et al., “Therapeutic effects of PPARα agonists on diabetic retinopathy in type 1 diabetes models,” Diabetes, vol. 62, no. 1, pp. 261–272, 2013.
View at: Publisher Site | Google Scholar
Z. Wang, E. Moran, L. Ding, R. Cheng, X. Xu, and J.-X. Ma, “PPARα regulates mobilization and homing of endothelial progenitor cells through the HIF-1α/SDF-1 pathway,” Investigative Ophthalmology & Visual Science, vol. 55, no. 6, pp. 3820–3832, 2014.
View at: Publisher Site | Google Scholar
E. Mazzon, C. Crisafulli, M. Galuppo, and S. Cuzzocrea, “Role of peroxisome proliferator-activated receptor-alpha in ileum tight junction alteration in mouse model of restraint stress,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 297, no. 3, pp. G488–G505, 2009.
View at: Publisher Site | Google Scholar
J. Varet, L. Vincent, P. Mirshahi et al., “Fenofibrate inhibits angiogenesis in vitro and in vivo,” Cellular and Molecular Life Sciences, vol. 60, no. 4, pp. 810–819, 2003.
View at: Publisher Site | Google Scholar
M. Meissner, M. Stein, C. Urbich et al., “PPARalpha activators inhibit vascular endothelial growth factor receptor-2 expression by repressing Sp1-dependent DNA binding and transactivation,” Circulation Research, vol. 94, no. 3, pp. 324–332, 2004.
View at: Publisher Site | Google Scholar
C. Swart, W. Haylett, C. Kinnear, G. Johnson, S. Bardien, and B. Loos, “Neurodegenerative disorders: dysregulation of a carefully maintained balance?” Experimental Gerontology, vol. 58, pp. 279–291, 2014.
View at: Publisher Site | Google Scholar
A. C. McKee, D. H. Daneshvar, V. E. Alvarez, and T. D. Stein, “The neuropathology of sport,” Acta Neuropathologica, vol. 127, no. 1, pp. 29–51, 2014.
View at: Publisher Site | Google Scholar
S. F. Abcouwer and T. W. Gardner, “Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment,” Annals of the New York Academy of Sciences, vol. 1311, no. 1, pp. 174–190, 2014.
View at: Publisher Site | Google Scholar
H. L. Ip and D. S. Liebeskind, “The future of ischemic stroke: flow from prehospital neuroprotection to definitive reperfusion,” Interventional Neurology, vol. 2, no. 3, pp. 105–117, 2014.
View at: Google Scholar
M. G. Scioli, A. Bielli, G. Arcuri, A. Ferlosio, and A. Orlandi, “Ageing and microvasculature,” Vascular Cell, vol. 6, no. 1, article 19, 2014.
View at: Publisher Site | Google Scholar
J. Folkman, “Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis,” The New England Journal of Medicine, vol. 333, no. 26, pp. 1757–1763, 1995.
View at: Google Scholar
G. A. Lutty, “Effects of diabetes on the eye,” Investigative Ophthalmology and Visual Science, vol. 54, no. 14, pp. ORSF81–ORSF87, 2013.
View at: Publisher Site | Google Scholar
W. R. Brown and C. R. Thore, “Review: cerebral microvascular pathology in ageing and neurodegeneration,” Neuropathology and Applied Neurobiology, vol. 37, no. 1, pp. 56–74, 2011.
View at: Publisher Site | Google Scholar
D. A. Antonetti, R. Klein, and T. W. Gardner, “Diabetic retinopathy,” The New England Journal of Medicine, vol. 366, no. 13, pp. 1227–1239, 2012.
View at: Publisher Site | Google Scholar
B. Poljsak, D. Šuput, and I. Milisav, “Achieving the balance between ROS and antioxidants: when to use the synthetic antioxidants,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 956792, 11 pages, 2013.
View at: Publisher Site | Google Scholar
S. Chakraborty, J. Bornhorst, T. T. Nguyen, and M. Aschner, “Oxidative stress mechanisms underlying parkinson's disease-associated neurodegeneration in C. elegans,” International Journal of Molecular Sciences, vol. 14, no. 11, pp. 23103–23128, 2013.
View at: Publisher Site | Google Scholar
G. E. Lang, “Mechanisms of retinal neurodegeneration as a result of diabetes mellitus,” Klinische Monatsblatter fur Augenheilkunde, vol. 230, no. 9, pp. 929–931, 2013.
View at: Publisher Site | Google Scholar
D. van Rossum and U.-K. Hanisch, “Microglia,” Metabolic Brain Disease, vol. 19, no. 3-4, pp. 393–411, 2004.
View at: Publisher Site | Google Scholar
M. J. Santos, R. A. Quintanilla, A. Toro et al., “Peroxisomal proliferation protects from β-amyloid neurodegeneration,” The Journal of Biological Chemistry, vol. 280, no. 49, pp. 41057–41068, 2005.
View at: Publisher Site | Google Scholar
T. Kukar, M. P. Murphy, J. L. Eriksen et al., “Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production,” Nature Medicine, vol. 11, no. 5, pp. 545–550, 2005.
View at: Publisher Site | Google Scholar
S. Brune, H. Kölsch, U. Ptok et al., “Polymorphism in the peroxisome proliferator-activated receptor α gene influences the risk for Alzheimer's disease,” Journal of Neural Transmission, vol. 110, no. 9, pp. 1041–1050, 2003.
View at: Publisher Site | Google Scholar
A. Sjölander, L. Minthon, N. Bogdanovic, A. Wallin, H. Zetterberg, and K. Blennow, “The PPAR-alpha gene in Alzheimer's disease: lack of replication of earlier association,” Neurobiology of Aging, vol. 30, no. 4, pp. 666–668, 2009.
View at: Publisher Site | Google Scholar
O. Hwang, “Role of oxidative stress in Parkinson's disease,” Experimental Neurobiology, vol. 22, no. 1, pp. 11–17, 2013.
View at: Publisher Site | Google Scholar
J. K. Barbiero, R. M. Santiago, D. S. Persike et al., “Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine,” Behavioural Brain Research, vol. 274, pp. 390–399, 2014.
View at: Publisher Site | Google Scholar
J. Ruiz-Medina, J. A. Flores, I. Tasset, I. Tunez, O. Valverde, and E. Fernandez-Espejo, “Alteration of neuropathic and visceral pain in female C57BL/6J mice lacking the PPAR-α gene,” Psychopharmacology, vol. 222, no. 3, pp. 477–488, 2012.
View at: Publisher Site | Google Scholar
J. LoVerme, R. Russo, G. la Rana et al., “Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha,” Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 3, pp. 1051–1061, 2006.
View at: Publisher Site | Google Scholar
M. Suardíaz, G. Estivill-Torrús, C. Goicoechea, A. Bilbao, and F. Rodríguez de Fonseca, “Analgesic properties of oleoylethanolamide (OEA) in visceral and inflammatory pain,” Pain, vol. 133, no. 1–3, pp. 99–110, 2007.
View at: Publisher Site | Google Scholar
N. Marx, B. Kehrle, K. Kohlhammer et al., “PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis,” Circulation Research, vol. 90, no. 6, pp. 703–710, 2002.
View at: Publisher Site | Google Scholar
A. Keech, P. Mitchell, P. Summanen et al., “Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial,” The Lancet, vol. 370, no. 9600, pp. 1687–1697, 2007.
View at: Publisher Site | Google Scholar
H. N. Ginsberg, M. B. Elam, L. C. Lovato et al., “Effects of combination lipid therapy in type 2 diabetes mellitus,” New England Journal of Medicine, vol. 362, no. 17, pp. 1563–1574, 2010.
View at: Publisher Site | Google Scholar
P. W. M. Kleikers, K. Wingler, J. J. R. Hermans et al., “NADPH oxidases as a source of oxidative stress and molecular target in ischemia/reperfusion injury,” Journal of Molecular Medicine, vol. 90, no. 12, pp. 1391–1406, 2012.
View at: Publisher Site | Google Scholar
E. Lyros, C. Bakogiannis, Y. Liu, and K. Fassbender, “Molecular links between endothelial dysfunction and neurodegeneration in Alzheimer's diseas,” Current Alzheimer Research, vol. 11, no. 1, pp. 18–26, 2014.
View at: Publisher Site | Google Scholar
A. Minagar, A. H. Maghzi, J. C. Mcgee, and S. J. Alexander, “Emerging roles of endothelial cells in multiple sclerosis pathophysiology and therapy,” Neurological Research, vol. 34, no. 8, pp. 738–745, 2012.
View at: Publisher Site | Google Scholar
A. A. F. Sima, W. Zhang, and G. Grunberger, “Type 1 diabetic neuropathy and C-peptide,” Experimental Diabesity Research, vol. 5, no. 1, pp. 65–77, 2004.
View at: Publisher Site | Google Scholar
C. Rask-Madsen and G. L. King, “Vascular complications of diabetes: mechanisms of injury and protective factors,” Cell Metabolism, vol. 17, no. 1, pp. 20–33, 2013.
View at: Publisher Site | Google Scholar
G. R. Drummond and C. G. Sobey, “Endothelial NADPH oxidases: which NOX to target in vascular disease?” Trends in Endocrinology & Metabolism, vol. 25, no. 9, pp. 452–463, 2014.
View at: Publisher Site | Google Scholar
M. Fisher, “Injuries to the vascular endothelium: vascular wall and endothelial dysfunction,” Reviews in Neurological Diseases, vol. 5, supplement 1, pp. S4–S11, 2008.
View at: Google Scholar
J. T. Durham and I. M. Herman, “Microvascular modifications in diabetic retinopathy,” Current Diabetes Reports, vol. 11, no. 4, pp. 253–264, 2011.
View at: Publisher Site | Google Scholar
N. Lois, R. V. McCarter, C. O'Neill, R. J. Medina, and A. W. Stitt, “Endothelial progenitor cells in diabetic retinopath,” Frontiers in Endocrinology, vol. 5, Article ID Article 44, 2014.
View at: Publisher Site | Google Scholar
J. Yellowlees Douglas, A. D. Bhatwadekar, S. Li Calzi et al., “Bone marrow-CNS connections: implications in the pathogenesis of diabetic retinopathy,” Progress in Retinal and Eye Research, vol. 31, no. 5, pp. 481–494, 2012.
View at: Publisher Site | Google Scholar
A. Jacob and J. J. Alexander, “Complement and blood–brain barrier integrity,” Molecular Immunology, vol. 61, no. 2, pp. 149–152, 2014.
View at: Publisher Site | Google Scholar
S. J. Hamilton, G. T. Chew, and G. F. Watts, “Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus,” Diabetes and Vascular Disease Research, vol. 4, no. 2, pp. 89–102, 2007.
View at: Publisher Site | Google Scholar
G. Russo, J. A. Leopold, and J. Loscalzo, “Vasoactive substances: nitric oxide and endothelial dysfunction in atherosclerosis,” Vascular Pharmacology, vol. 38, no. 5, pp. 259–269, 2002.
View at: Publisher Site | Google Scholar
M. E. Widlansky, N. Gokce, J. F. Keaney Jr., and J. A. Vita, “The clinical implications of endothelial dysfunction,” Journal of the American College of Cardiology, vol. 42, no. 7, pp. 1149–1160, 2003.
View at: Publisher Site | Google Scholar
J. Chou, S. Rollins, and A. A. Fawzi, “Role of endothelial cell and pericyte dysfunction in diabetic retinopathy: review of techniques in rodent models,” in Retinal Degenerative Diseases, vol. 801 of Advances in Experimental Medicine and Biology, pp. 669–675, Springer, New York, NY, USA, 2014.
View at: Publisher Site | Google Scholar
A. Hiukka, J. Westerbacka, E. S. Leinonen et al., “Long-term effects of fenofibrate on carotid intima-media thickness and augmentation index in subjects with type 2 diabetes mellitus,” Journal of the American College of Cardiology, vol. 52, no. 25, pp. 2190–2197, 2008.
View at: Publisher Site | Google Scholar
J.-C. Hogue, B. Lamarche, A. J. Tremblay, J. Bergeron, C. Gagné, and P. Couture, “Differential effect of atorvastatin and fenofibrate on plasma oxidized low-density lipoprotein, inflammation markers, and cell adhesion molecules in patients with type 2 diabetes mellitus,” Metabolism: Clinical and Experimental, vol. 57, no. 3, pp. 380–386, 2008.
View at: Publisher Site | Google Scholar
A. Avogaro, M. Miola, A. Favaro et al., “Gemfibrozil improves insulin sensitivity and flow-mediated vasodilatation in type 2 diabetic patients,” European Journal of Clinical Investigation, vol. 31, no. 7, pp. 603–609, 2001.
View at: Publisher Site | Google Scholar
M. E. Poynter and R. A. Daynes, “Peroxisome proliferator-activated receptor α activation modulates cellular redox status, represses nuclear factor-κB signaling, and reduces inflammatory cytokine production in aging,” Journal of Biological Chemistry, vol. 273, no. 49, pp. 32833–32841, 1998.
View at: Publisher Site | Google Scholar
P. Delerive, K. de Bosscher, S. Besnard et al., “Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1,” The Journal of Biological Chemistry, vol. 274, no. 45, pp. 32048–32054, 1999.
View at: Publisher Site | Google Scholar
R. Simó and C. Hernández, “Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives,” Trends in Endocrinology & Metabolism, vol. 25, no. 1, pp. 23–33, 2014.
View at: Publisher Site | Google Scholar
B. V. Zlokovic, “Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders,” Nature Reviews Neuroscience, vol. 12, no. 12, pp. 723–738, 2011.
View at: Publisher Site | Google Scholar
M. P. Bhatt, Y.-C. Lim, and K.-S. Ha, “C-peptide replacement therapy as an emerging strategy for preventing diabetic vasculopathy,” Cardiovascular Research, vol. 104, no. 2, pp. 234–244, 2014.
View at: Publisher Site | Google Scholar
R. Jin, G. Yang, and G. Li, “Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator,” Neurobiology of Disease, vol. 38, no. 3, pp. 376–385, 2010.
View at: Publisher Site | Google Scholar
S. F. Rimoldi, M. Yuzefpolskaya, Y. Allemann, and F. Messerli, “Flash pulmonary edema,” Progress in Cardiovascular Diseases, vol. 52, no. 3, pp. 249–259, 2009.
View at: Publisher Site | Google Scholar
Q. Xu, T. Qaum, and A. P. Adamis, “Sensitive blood-retinal barrier breakdown quantitation using Evans blue,” Investigative Ophthalmology & Visual Science, vol. 42, no. 3, pp. 789–794, 2001.
View at: Google Scholar
T. Frey and D. A. Antonetti, “Alterations to the blood-retinal barrier in diabetes: cytokines and reactive oxygen species,” Antioxidants and Redox Signaling, vol. 15, no. 5, pp. 1271–1284, 2011.
View at: Publisher Site | Google Scholar
W. Huang, L. Chen, B. Zhang, M. Park, and M. Toborek, “PPAR agonist-mediated protection against HIV Tat-induced cerebrovascular toxicity is enhanced in MMP-9-deficient mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 34, no. 4, pp. 646–653, 2014.
View at: Publisher Site | Google Scholar
W. Huang, Y. E. Sung, I. E. András, B. Hennig, and M. Toborek, “PPARα and PPARγ attenuate HIV-induced dysregulation of tight junction proteins by modulations of matrix metalloproteinase and proteasome activities,” The FASEB Journal, vol. 23, no. 5, pp. 1596–1606, 2009.
View at: Publisher Site | Google Scholar
C. Mysiorek, M. Culot, L. Dehouck et al., “Peroxisome proliferator-activated receptor-α activation protects brain capillary endothelial cells from oxygen-glucose deprivation-induced hyperpermeability in the blood-brain barrier,” Current Neurovascular Research, vol. 6, no. 3, pp. 181–193, 2009.
View at: Publisher Site | Google Scholar
S. Takeda, N. Sato, and R. Morishita, “Systemic inflammation, blood-brain barrier vulnerability and cognitive/non-cognitive symptoms in Alzheimer disease: relevance to pathogenesis and therapy,” Frontiers in Aging Neuroscience, vol. 6, article 171, 2014.
View at: Publisher Site | Google Scholar
H. Lee and I. S. Pienaar, “Disruption of the blood-brain barrier in parkinson's disease: curse or route to a cure?” Frontiers in Bioscience, vol. 19, no. 2, pp. 272–280, 2014.
View at: Publisher Site | Google Scholar
S. C. Thal and W. Neuhaus, “The blood-brain barrier as a target in traumatic brain injury treatment,” Archives of Medical Research, 2014.
View at: Publisher Site | Google Scholar
G. Tremolada, C. Del Turco, R. Lattanzio et al., “The role of angiogenesis in the development of proliferative diabetic retinopathy: impact of intravitreal anti-VEGF treatment,” Experimental Diabetes Research, vol. 2012, Article ID 728325, 8 pages, 2012.
View at: Publisher Site | Google Scholar
K. Mittal, J. Ebos, and B. Rini, “Angiogenesis and the tumor microenvironment: vascular endothelial growth factor and beyond,” Seminars in Oncology, vol. 41, no. 2, pp. 235–251, 2014.
View at: Publisher Site | Google Scholar
U. Sadat, F. A. Jaffer, M. A. van Zandvoort, S. J. Nicholls, D. Ribatti, and J. H. Gillard, “Inflammation and neovascularization intertwined in atherosclerosis: imaging of structural and molecular imaging targets,” Circulation, vol. 130, no. 9, pp. 786–794, 2014.
View at: Publisher Site | Google Scholar
A. Salam, R. Mathew, and S. Sivaprasad, “Treatment of proliferative diabetic retinopathy with anti-VEGF agents,” Acta Ophthalmologica, vol. 89, no. 5, pp. 405–411, 2011.
View at: Publisher Site | Google Scholar
D. Cervia, E. Catalani, M. Dal Monte, and G. Casini, “Vascular endothelial growth factor in the ischemic retina and its regulation by somatostatin,” Journal of Neurochemistry, vol. 120, no. 5, pp. 818–829, 2012.
View at: Publisher Site | Google Scholar
M. N. Gao and Y. Li, “The regulation of VEGFs/VEGFRs in tumor angiogenesis by Wnt/beta-catenin and NF-kappaB signal pathway,” Sheng Li Ke Xue Jin Zhan, vol. 44, no. 1, pp. 72–74, 2013.
View at: Google Scholar
S. L. Calzi, M. B. Neu, L. C. Shaw, J. L. Kielczewski, N. I. Moldovan, and M. B. Grant, “EPCs and pathological angiogenesis: when good cells go bad,” Microvascular Research, vol. 79, no. 3, pp. 207–216, 2010.
View at: Publisher Site | Google Scholar
A. R. Vasudevan and P. H. Jones, “Effective use of combination lipid therapy,” Current Cardiology Reports, vol. 7, no. 6, pp. 471–479, 2005.
View at: Publisher Site | Google Scholar
R.-D. Ting, A. C. Keech, P. L. Drury et al., “Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD study,” Diabetes Care, vol. 35, no. 2, pp. 218–225, 2012.
View at: Publisher Site | Google Scholar
P. Balakumar, R. Varatharajan, Y. H. Nyo et al., “Fenofibrate and dipyridamole treatments in low-doses either alone or in combination blunted the development of nephropathy in diabetic rats,” Pharmacological Research, vol. 90, pp. 36–47, 2014.
View at: Publisher Site | Google Scholar
Y. A. Hong, J. H. Lim, M. Y. Kim et al., “Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1α in db/db mice,” PLoS ONE, vol. 9, no. 5, Article ID e96147, 2014.
View at: Publisher Site | Google Scholar

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Copyright © 2015 Elizabeth P. Moran and Jian-xing Ma. 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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