Mechanistic insights into hyperuricemia-associated renal abnormalities with special emphasis on epithelial-to-mesenchymal transition: Pathologic implications and putative pharmacologic targets.

Though the pathogenesis of hyperuricemia-induced renal complications is not precisely known, hyperuricemia has been recognized as an independent risk factor for renal disease. While the clinical implication of hyperuricemia in renal disease has been a contemporary topic of debate, growing body of bench and clinical evidences certainly suggest a causative role of high uric acid in renal abnormalities by implicating diverse pathologic and molecular mechanisms. Urate crystals after having deposited in the kidney could cause hyperuricemia nephropathy leading to glomerular hypertrophy and tubulointerstitial fibrosis, while high serum uric acid might predict progressive renal damage and dysfunction. Hyperuricemia could be associated with manifestation of tubular injury and macrophage infiltration as well as an increased expression of inflammatory mediators. This review sheds light on the mechanistic aspects pertaining to hyperuricemia-associated renal abnormalities. Besides, the renal detrimental actions of high uric acid possibly mediated through its potential role on oxidative stress, renal inflammation, endothelial dysfunction, glycocalyx shedding, endothelial-to-mesenchymal transition and more specifically on the renal epithelial-to-mesenchymal transition have been addressed. Moreover, this review discusses a number of potential targets such as endothelin-1, TLR4/NF-kB, PI3K/p-Akt, Wnt5a/Ror2, NLRP3 inflammasome, NADPH oxidase, ERK1/2, enhancer of zeste homolog 2, serum response factor and Smad3/TGF-ß signalling pathways, among others, implicated in hyperuricemia-associated renal abnormalities. This review finally apprises a number of bench and clinical studies which supporting a notion that the pharmacologic reduction of high uric acid might have a therapeutic value in the management of renal abnormalities, with an emphasis on febuxostat and its renal pleiotropic actions.

A potential role of the renin-angiotensin-aldosterone system in epithelial-to-mesenchymal transition-induced renal abnormalities: Mechanisms and therapeutic implications.

Epithelial-to-mesenchymal transition (EMT) is an orchestrated event where epithelial cells progressively undergo biochemical changes and transition into mesenchymal-like cells by gradually losing their epithelial characteristics. EMT plays a crucial pathologic role in renal abnormalities, especially renal fibrosis. A number of bench studies suggest the potential involvement of renin-angiotensin-aldosterone system (RAAS) in renal EMT process and associated renal abnormalities. EMT appears to be an important pathologic mechanism for the deleterious renal effects of angiotensin II and aldosterone, the two major RAAS components. Mechanistically, the renal RAAS-TGF-ß-Smad3 signalling pathway plays an important pathologic role in EMT-associated renal abnormalities. Intriguingly, the RAAS antagonists such as losartan, telmisartan, eplerenone, and spironolactone have the potential to prevent renal EMT in bench studies. This review describes the key mechanistic role of RAAS overactivation in EMT-induced renal abnormalities. Moreover, drugs interrupting the RAAS at different levels in the cascade ameliorating the EMT-associated renal abnormalities are described.

Molecular targets of fenofibrate in the cardiovascular-renal axis: A unifying perspective of its pleiotropic benefits.

The activation of peroxisome proliferator-activated receptor α (PPARα) is a key pharmacological drug target for dyslipidemic management. Dyslipidemia is associated with abnormal serum lipid profiles viz. elevated total cholesterol, high triglyceride, elevated low-density lipoprotein cholesterol, and reduced high-density lipoprotein cholesterol levels. Fenofibrate, a third-generation fibric acid derivative, is an activator of PPARα indicated for the treatment of mixed dyslipidemia and hypertriglyceridemia in adults. Fenofibrate is considered an important lipid-lowering medication employed in patients afflicted with atherogenic dyslipidemia. Intriguingly, recent bench studies have demonstrated an array of cardiovascular and renal pleiotropic beneficial activities of fenofibrate, besides its foremost lipid-lowering action. The activation of PPARα by fenofibrate could negatively regulate the cardiomyocyte hypertrophy. In addition, fenofibrate has been suggested to have a protective effect against experimental ischemia/reperfusion injury in the myocardium in part via endoplasmic reticulum stress inhibition. Fenofibrate has also been shown to suppress arrhythmias in isolated rat hearts subjected to ischemic/reperfusion-induced cardiac injury. Moreover, in a rat model of metabolic syndrome and myocardial ischemia, fenofibrate therapy has been shown to restore antioxidant protection and improve myocardial insulin resistance. Furthermore, studies have highlighted the pleiotropic vascular endothelial protective and antihypertensive actions of fenofibrate. Interestingly, recent bench studies have demonstrated renoprotective actions of fenofibrate by implicating diverse mechanisms. This review sheds light on the current perspectives and molecular mechanistic aspects pertaining to the cardiovascular pleiotropic actions of fenofibrate. Additionally, the renal pleiotropic actions of fenofibrate by focusing its possible modulatory role on renal fibrosis, inflammation and renal epithelial-to-mesenchymal transition have been enlightened.

A Contemporary Overview of PPARα/γ Dual Agonists for the Management of Diabetic Dyslipidemia.

BACKGROUND: Diabetes mellitus and concomitant dyslipidemia, being referred to as 'diabetic dyslipidemia', are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated. CONCLUSION: Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.

Fenofibrate attenuates impaired ischemic preconditioning-mediated cardioprotection in the fructose-fed hypertriglyceridemic rat heart.

We investigated in this study whether or not the ischemic preconditioning (IPC)-mediated cardioprotective effect against ischemia-reperfusion (I/R) injury exists in the fructose-fed hypertriglyceridemic (HTG) rat heart. Langendorff-perfused normal and fructose-fed (10 % w/v in drinking water, 8 weeks) HTG rat hearts were subjected to 30-min global ischemia and 120-min reperfusion. IPC protocol included four brief episodes (5 min each) of ischemia and reperfusion. Myocardial infarct size using triphenyltetrazolium chloride staining, markers of cardiac injury such as lactate dehydrogenase (LDH) and creatine kinase (CK-MB) release, coronary flow rate (CFR), and myocardial oxidative stress were assessed. High degree of myocardial I/R injury, by means of significant myocardial infarct size, elevated coronary LDH and CK-MB release, reduced CFR, and high oxidative stress, was noted in the HTG rat heart as compared to the normal rat heart. The IPC-mediated cardioprotection against I/R injury was markedly impaired in the HTG rat heart as compared to the normal rat heart. Interestingly, pharmacological reduction of triglycerides using 8-week treatment protocol with fenofibrate (80 mg/kg/day, p.o.) restored the IPC effect in the HTG rat heart that was blunted by coinfusion, during the IPC reperfusion protocol, of a specific inhibitor of phosphoinositide-3-kinase (PI3-K), wortmannin (100 nM). The IPC failed to protect the HTG rat heart against I/R injury. Fenofibrate treatment reduced high triglycerides in the fructose-fed HTG rat and subsequently restored the cardioprotective effect of IPC.

Adenosine transport blockade restores attenuated cardioprotective effects of adenosine preconditioning in the isolated diabetic rat heart: potential crosstalk with opioid receptors.

Considering the reduced ability of cardiac fibroblasts to release adenosine and increased ability of interstitial adenosine uptake during diabetes mellitus, the present study investigated the effect of adenosine preconditioning and the existence of cross-talk with opioid receptor activation in the diabetic rat heart subjected to ischemia-reperfusion (I/R). Langendorff-perfused normal and streptozotocin (65 mg/kg, i.p., once)-administered diabetic (after 8-weeks) rat hearts were subjected to 30-min global ischemia and 120-min reperfusion. Myocardial infarct size using triphenyltetrazolium chloride staining, markers of cardiac injury such as lactate dehydrogenase (LDH) and creatine kinase (CK-MB) release, coronary flow rate (CFR) and myocardial oxidative stress were assessed. The diabetic rat heart showed high degree of I/R injury with increased LDH and CK-MB release, high oxidative stress and reduced CFR as compared to the normal rat heart. The adenosine preconditioning (10 µM) afforded cardioprotection against I/R injury in the normal rat heart that was prevented by naloxone (100 µM) pre-treatment. Conversely, adenosine preconditioning-induced cardioprotection was abolished in the diabetic rat heart. However, co-administration of dipyridamole (100 µM), adenosine reuptake inhibitor, markedly restored the cardioprotective effect of adenosine preconditioning in the diabetic rat heart, and this effect was also abolished by naloxone pre-treatment. The reduced myocardial availability of extracellular adenosine might explain the inability of adenosine preconditioning to protect the diabetic myocardium. The pharmacological elevation of extracellular adenosine restores adenosine preconditioning-mediated cardioprotection in the diabetic myocardium by possibly involving opioid receptor activation.

Differential effects of low-dose fenofibrate treatment in diabetic rats with early onset nephropathy and established nephropathy.

We have previously shown that low-dose fenofibrate treatment has an ability to prevent diabetes-induced nephropathy in rats. We investigated here the comparative pre- and post-treatment effects of low-dose fenofibrate (30 mg/kg/day p.o.) in diabetes-induced onset of nephropathy. Rats were made diabetics by single administration of streptozotocin (STZ, 55 mg/kg i.p.). The development of diabetic nephropathy was assessed biochemically and histologically. Moreover, lipid profile and renal oxidative stress were assessed. Diabetic rats after 8 weeks of STZ-administration developed apparent nephropathy by elevating serum creatinine, blood urea nitrogen and microproteinuria, and inducing glomerular-capsular wall distortion, mesangial expansion and tubular damage and renal oxidative stress. Fenofibrate (30 mg/kg/day p.o., 4 weeks) pretreatment (4 weeks after STZ-administration) markedly prevented diabetes-induced onset of diabetic nephropathy, while the fenofibrate (30 mg/kg/day p.o., 4 weeks) post-treatment (8 weeks after STZ-administration) was less-effective. However, both pre-and post fenofibrate treatments were effective in preventing diabetes-induced renal oxidative stress and lipid alteration in diabetic rats though the pretreatment was slightly more effective. Conversely, both pre-and post fenofibrate treatments did not alter elevated glucose levels in diabetic rats. It may be concluded that diabetes-induced oxidative stress and lipid alteration, in addition to a marked glucose elevation, play a detrimental role in the onset of nephropathy in diabetic rats. The pretreatment with low-dose fenofibrate might be a potential therapeutic approach in preventing the onset of nephropathy in diabetic subjects under the risk of renal disease induction. However, low-dose fenofibrate treatment might not be effective in treating the established nephropathy in diabetic subjects.

Fish oil blunted nicotine-induced vascular endothelial abnormalities possibly via activation of PPARγ-eNOS-NO signals.

Nicotine exposure is associated with an induction of vascular endothelial dysfunction (VED), a hallmark of various cardiovascular disorders. The present study investigated the effect of fish oil in nicotine-induced experimental VED. VED was assessed by employing isolated aortic ring preparation, estimating aortic and serum nitrite/nitrate, aortic superoxide anion generation, and serum TBARS, and carrying out electron microscopic and histological studies of thoracic aorta. Nicotine (2 mg/kg/day, i.p., 4 weeks) administration produced VED in rats by attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentration, impairing endothelial integrity, and inducing vascular oxidative stress. Treatment with fish oil (2 mL/kg/day p.o., 4 weeks) markedly prevented nicotine-induced endothelial functional and structural abnormalities and oxidative stress. However, administration of GW9662, a selective inhibitor of PPARγ, to a significant degree attenuated fish oil-associated anti-oxidant action and vascular endothelial functional and structural improvements. Intriguingly, in vitro incubation of L-NAME (100 µM), an inhibitor of nitric oxide synthase (NOS), markedly attenuated fish oil-induced improvement in endothelium-dependent relaxation in the aorta of nicotine-administered rats. Nicotine administration altered the lipid profile by increasing serum total cholesterol, which was significantly prevented by fish oil treatment. The vascular protective potential of fish oil in preventing nicotine-induced VED may pertain to its additional properties (besides its lipid-lowering effect) such as activation of PPARγ and subsequent possible activation of endothelial NOS and generation of nitric oxide, and consequent reduction in oxidative stress.

Possible involvement of PPARγ-associated eNOS signaling activation in rosuvastatin-mediated prevention of nicotine-induced experimental vascular endothelial abnormalities.

Nicotine exposure via cigarette smoking and tobacco chewing is associated with vascular complications. The present study investigated the effect of rosuvastatin in nicotine (2 mg/kg/day, i.p., 4 weeks)-induced vascular endothelial dysfunction (VED) in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating aortic and serum nitrite/nitrate concentration. Further, scanning electron microscopy and hematoxylin-eosin staining of thoracic aorta were performed to assess the vascular endothelial integrity. Moreover, oxidative stress was assessed by estimating aortic superoxide anion generation and serum thiobarbituric acid-reactive substances. The nicotine administration produced VED by markedly reducing acetylcholine-induced endothelium-dependent relaxation, impairing the integrity of vascular endothelium, decreasing aortic and serum nitrite/nitrate concentration, increasing oxidative stress, and inducing lipid alteration. However, treatment with rosuvastatin (10 mg/kg/day, i.p., 4 weeks) markedly attenuated nicotine-induced vascular endothelial abnormalities, oxidative stress, and lipid alteration. Interestingly, the co-administration of peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662 (1 mg/kg/day, i.p., 2 weeks) submaximally, significantly prevented rosuvastatin-induced improvement in vascular endothelial integrity, endothelium-dependent relaxation, and nitrite/nitrate concentration in rats administered nicotine. However, GW9662 co-administration did not affect rosuvastatin-associated vascular anti-oxidant and lipid-lowering effects. The incubation of aortic ring, isolated from rosuvastatin-treated nicotine-administered rats, with L-NAME (100 µM), an inhibitor of nitric oxide synthase (NOS), significantly attenuated rosuvastatin-induced improvement in acetylcholine-induced endothelium-dependent relaxation. Rosuvastatin prevents nicotine-induced vascular endothelial abnormalities by activating PPARγ and endothelial NOS signaling pathways. Moreover, the PPARγ-independent anti-oxidant and lipid-lowering effects of rosuvastatin might additionally play a role in the improvement of vascular endothelial function.

The combined strategy with PPARα agonism and AT1 receptor antagonism is not superior relative to their individual treatment approach in preventing the induction of nephropathy in the diabetic rat.

We have previously shown that the low-dose combination of fenofibrate and rosiglitazone might halt the progression of diabetes-induced nephropathy in rats. The present study investigated the combined effect of fenofibrate (PPARα agonist) and telmisartan (AT1 receptor antagonist) in diabetes-induced onset of nephropathy in rats. The single administration of streptozotocin (STZ, 55 mg/kg i.p.) produced diabetes mellitus, which subsequently produced nephropathy in 8 weeks by markedly elevating serum creatinine, blood urea nitrogen and microproteinuria. In addition, histopathological studies revealed the development of renal structural abnormalities such as mesangial expansion, glomerular and tubular damage. Moreover, diabetes-induced nephropathy was accompanied with high renal oxidative stress and lipid alteration. Treatment with fenofibrate (80 mg/kg/day, p.o., 4 weeks) and telmisartan (10 mg/kg/day, p.o., 4 weeks) either alone or in combination did not affect the elevated glucose levels in diabetic rats. Albeit treatment with fenofibrate normalizes the altered lipid profile in diabetic rats, telmisartan treatment has no effect on it. Treatment with fenofibrate and telmisartan either alone or in combination markedly prevented diabetes-induced onset of nephropathy and renal oxidative stress. Their combination was as good as to their individual treatment, but not superior in attenuating the diabetes-induced nephropathy and renal oxidative stress. It may be concluded that diabetes-induced oxidative stress and lipid alteration, besides hyperglycemia, could play a key role in the induction of nephropathy. Fenofibrate and telmisartan individual treatment was equipotent in preventing the onset of diabetes-induced experimental nephropathy, while their combination did not afford additional benefits in preventing the disease induction of the diabetic kidney.

Telmisartan in the management of diabetic nephropathy: a contemporary view.

Diabetic nephropathy, a complex disorder with heterogeneous etiologies, remains one of the most threatening diseases worldwide. There were around 177 million people with diabetes mellitus worldwide, and it has been estimated to be increased to 360 million by 2030. Given that about 20-30% of these people develop diabetic nephropathy, the present treatment protocols primarily aim for an efficient glucose and blood pressure control to arrest the initiation and progression of diabetic nephropathy. The treatment of diabetic nephropathy near the beginning at microalbuminuria stage with angiotensin-II-AT1 receptor blockers (ARBs) improves blood pressure control and halts disease progression of diabetic nephropathy. In fact, ARBs exert renoprotective effects independently of their blood pressure lowering effect, as they have direct defensive action on the diabetic kidney. Indubitably, it would be better if an ARB has both glucose-lowering and blood pressure controlling potentials efficiently. Intriguingly, telmisartan has such possessions considering its dual role of AT1 receptor blocking action and peroxisome proliferator-activated receptor gamma (PPARγ) partial agonistic property. The additional PPARγ agonistic potential of telmisartan could make it a distinctive intervention in the ARB class to prevent the progression of diabetic nephropathy through activation of PPARγ-mediated insulin sensitization, and renal anti-inflammatory and anti-oxidant actions. Indeed, telmisartan reduced insulin resistance and glucose intolerance, and halted the progressive renal dysfunction associated with diabetic nephropathy by inhibiting the incidence of albuminuria, and preventing the progression of glomerulosclerosis, renal interstitial inflammation and fibrosis. This review will discuss the current status of therapeutic potentials of telmisartan in treating diabetic nephropathy.

Are PPAR alpha agonists a rational therapeutic strategy for preventing abnormalities of the diabetic kidney?

The uncontrolled diabetes mellitus may result in the induction of diabetic nephropathy, one of the detrimental microvascular complications of diabetes mellitus. Diabetic nephropathy is associated with glomerular hypertrophy, glomerulosclerosis, tubulointerstitial fibrosis, mesangial cell expansion, followed by albuminuria and reduction in glomerular filtration rate. Indeed, no promising therapeutic options are available in the present clinical scenario to manage efficiently the diabetic nephropathy. Nevertheless, angiotensin converting enzyme inhibitors and angiotensin-II-AT(1) receptor blockers are currently employed to improve structural and functional status of the diabetic kidney. These interventions, however, are not optimal in improving overall outcomes of diabetic nephropathy. Hence, there is a continuing need of developing promising therapeutic interventions to manage this insidious condition adequately. Recent bench and clinical studies strongly suggest the potentials of peroxisome proliferator-activated receptor alpha (PPARα) agonists in the management of diabetic nephropathy by keeping the view that renal lipid accumulation-induced lipotoxicity is one of risk factors for nephropathy during chronic diabetes mellitus. As inflammation, oxidative stress and dyslipidemia are common consequences of renal dysfunction, PPARα agonists could serve as promising therapeutic agents for controlling the progression of diabetic nephropathy. In fact, fenofibrate, a hypolipidemic agent acts as a PPARα agonist, reduced renal lipotoxicity, inflammation, fibrosis and oxidative stress, and subsequently prevented the symptoms of diabetic nephropathy. However, fenofibrate has been shown to cause renal dysfunction in established renal disorders. The present review addressed the rationale of employing PPARα agonists in the management of diabetic nephropathy.

Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins?

Statins are widely used in the treatment of dyslipidemia and associated cardiovascular abnormalities including atherosclerosis, hypertension and coronary heart disease. Needless to mention, statins have cholesterol-lowering effects by means of inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme of cholesterol biosynthesis. Besides cholesterol-lowering effects, statins possess pleiotropic anti-inflammatory, anti-oxidant, anti-platelet and anti-fibrotic properties, which may additionally play imperative roles in statins-mediated cardiovascular protection. However, the precise mechanisms involved in the cardiovascular defensive potential of statins have not completely been elucidated. Intriguingly, a considerable number of studies demonstrated the potential modulatory role of statins on endothelial nitric oxide synthase (eNOS), a key enzyme involved in the regulation of cardiovascular function by generating endothelium-derived relaxing factor (often represented 'nitric oxide'). Worthy of note is that vascular generation of nitric oxide has beneficial anti-inflammatory, anti-platelet and vasodilatory actions. The upregulation of eNOS by statins is mediated through inhibition of synthesis of isoprenoids and subsequent prevention of isoprenylation of small GTPase Rho, whereas statin-induced activation of eNOS is mediated through activation of phosphotidylinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) signals. Additionally, statins enhance eNOS activation by abrogating caveolin-1 expression in vascular endothelium. In light of this view-point, we suggest in this review that eNOS upregulation and activation, in part, could play a fundamental role in the cardiovascular defensive potential of statins. The eNOS modulatory role of statins may have an imperative influence on the functional regulation of cardiovascular system and may offer new perspectives for the better use of statins in ameliorating cardiovascular disorders.

Interplay between statins and PPARs in improving cardiovascular outcomes: a double-edged sword?

Statins are best-selling medications in the management of high cholesterol and associated cardiovascular complications. They inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase in order to prevent disproportionate cholesterol synthesis. Statins slow the progression of atherosclerosis, prevent the secondary cardiovascular events and improve the cardiovascular outcomes in patients with elevated cholesterol levels. The underlying mechanisms pertaining to the cardioprotective role of statins are linked with numerous pleiotropic actions including inhibition of inflammatory events and improvement of endothelial function, besides an effective cholesterol-lowering ability. Intriguingly, recent studies suggest possible interplay between statins and nuclear transcription factors like PPARs, which should also be taken into consideration while analysing the potential of statins in the management of cardiovascular complications. It could be suggested that statins have two major roles: (i) a well-established cholesterol-lowering effect through inhibition of HMG-CoA-reductase; (ii) a newly explored PPAR-activating property, which could mediate most of cardiovascular protective pleiotropic effects of statins including anti-inflammatory, antioxidant and anti-fibrotic properties. The present review addressed the underlying principles pertaining to the modulatory role of statins on PPARs.

Pleiotropic actions of fenofibrate on the heart.

Fenofibrate is a third-generation fibric acid derivative employed clinically as a hypolipidemic agent to lessen the risk caused by atherosclerosis. Dyslipidemia is a condition associated with elevated levels of low-density lipoproteins (LDL), very low-density lipoproteins (VLDL) and triglycerides, and reduced levels of high-density lipoproteins (HDL) in the circulation. Fenofibrate has an ability to diminish LDL, VLDL and triglycerides and pertinently augment HDL, and thus it is used to manage dyslipidemia. The lipid lowering effects of fenofibrate are classically mediated via an activation of peroxisome proliferator-activated receptor-alpha (PPAR-α). Recent studies demonstrated numerous pleiotropic effects of fenofibrate on the heart that afford direct myocardial protection besides its lipid lowering effects. Fenofibrate has an additional potential to prevent the induction and progression of hypertensive heart damage, cardiac hypertrophy, heart failure, myocarditis, lipotoxic cardiomyopathy and vascular endothelial dysfunction-associated cardiovascular abnormalities. In this review, we critically discussed recently identified pleiotropic actions of fenofibrate on the heart. Moreover, the novel cardioprotective effects of fenofibrate against various cardiac disorders have been delineated.