Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

Vera, Trinity; Taylor, Montoya; Bohman, Quinn; Flasch, Averia K.; Roman, Richard J.; Stec, David E.

doi:10.1161/01.hyp.0000153317.06072.2e

Cited by 49 publications

(58 citation statements)

References 34 publications

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“…20-HETE is currently characterized as a prohypertensive eicosanoid, and has the potential to play a dual role in the regulation of blood pressure by virtue of its ability to induce contraction, as well as to inhibit sodium reabsorption (reviewed in Reference 59). The global consequences of enhanced renal 20-HETE production seem more closely related to prevention than aggravation of hypertension, as increased renal 20-HETE production after fibrate treatment has been linked to CYP -hydroxylase induction and attenuation of angiotensin II-induced, 60 as well as desoxycorticosterone acetate salt-induced hypertension 61 in mice. Also, inhibitors of 20-HETE formation promote salt-sensitive hypertension in rats.…”

Section: Eets and Hypertensionmentioning

confidence: 99%

Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function

2006

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Abstract-Epoxyeicosatrienoic acids (EETs) are epoxides of arachidonic acid generated by cytochrome P450 (CYP) epoxygenases. The activation of CYP epoxygenases in endothelial cells is an important step in the NO and prostacyclin-independent vasodilatation of several vascular beds, and EETs have been identified as an endotheliumderived hyperpolarizing factor. However, EETs also exert membrane potential-independent effects and modulate several signaling cascades that affect endothelial cell proliferation and angiogenesis. This review summarizes the role of CYP-derived EETs in endothelium-derived hyperpolarizing factor-mediated responses and highlights the evidence indicating that EETs are important second messengers involved in endothelial cell signaling pathways related to angiogenesis. (Hypertension. 2006;47:629-633.)Key Words: calcium channels Ⅲ endothelium-derived factors Ⅲ hypertension Ⅲ vasodilatation T here is now considerable evidence linking the metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes with the regulation of vascular homeostasis and tone, as well as renal function. The enzymes in question fall into 2 classes: (1) the epoxygenases, which generate epoxyeicosatrienoic acids (EETs); and (2) the /-1 hydroxylases, which generate 20-hydroxyeicosatetraenoic acid (20-HETE). EETs and Endothelium-Derived Hyperpolarizing FactorInterest in the vascular actions of EETs was initially related to their identification as an endothelium-derived hyperpolarizing factor (EDHF), that is, compounds responsible for the NO and prostacyclin-independent but endothelium-dependent vasodilatation of some vascular beds. There is now convincing evidence indicating that the hyperpolarizing factor produced by coronary and renal arteries from several species (humans, pigs, cows, dogs, rats, and rabbits) displays characteristics similar to those of a cytochrome CYP-derived metabolite of arachidonic acid. 1 A CYP-dependent, EDHF response has also been described in other human arteries/vascular beds including the mammary artery, 2 the forearm vasculature, 3 and thigh skeletal muscle circulation. 4 However, the EDHFmediated relaxations in human mesenteric arteries 5 and renal arteries 6 appear to be independent of CYP activity. For those following the "EDHF story," the literature has been highly confusing, and for several years the field seemed caught in a pantomime of "it is" versus "it isn't" reports. One reason for the confusion was that although some EDHFmediated responses could be attributed to a CYP-derived metabolite of arachidonic acid, there were clearly other responses that occurred entirely independently of the activation of a CYP enzyme. For comprehensive reviews on the nature of the different EDHFs, the reader should consult references. [7][8][9] Part of the reason for some of the controversy was that EETs were initially reported to initiate smooth muscle hyperpolarization by activating iberiotoxin-sensitive large conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels, 10 whereas EDHFdependent relaxation was mor...

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Section: Eets and Hypertensionmentioning

confidence: 99%

Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function

2006

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“…Our previous studies observed an increased plasma 8-isoprostane level and NAD(P)H oxidase activity in L-NAME-induced high blood pressure, which was blunted by bezafibrate [2] . In a similar study fenofibrate reduced blood pressure in mice with an implanted osmotic mini-pump releasing AII through increased cytochrome P450 metabolite [33,34] . Other groups in our laboratory have also reported lowering effect of clofibrate on L-NAME induced high blood pressure in rats through modulation of NO and AII receptor [30] .…”

Section: Discussionmentioning

confidence: 99%

PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats

Yousefipour

Newaz

2014

Acta Pharmacol Sin

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Aim: Peroxisome proliferator activated receptors (PPARs) are nuclear transcription factors that regulate numerous genes influencing blood pressure. The aim of this study was to examine the effects of clofibrate, a PPARα ligand, on blood pressure in spontaneously hypertensive rats (SHR). Methods: Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), 8-9 weeks old, were randomly allocated into groups treated with vehicle or clofibrate (250 mg·kg -1 ·d -1 , ip for 21 d). Systolic blood pressure (SBP) was measured before and after the study period using tail-cuff plethysmography. Rats were sacrificed under anesthesia and blood, urine and tissue samples were processed for subsequent analysis. Results: SHR rats showed significantly higher SBP compared with WKY rats (198±6 mmHg vs 93±7 mmHg), and a 3-fold increase in urinary protein excretion. Clofibrate treatment reduced SBP by 26%±2% and proteinuria by 43%±9% in SHR but not in WKY rats. The urinary nitrite/nitrate excretion in SHR rats was nearly 2-fold greater than that in WKY, and was further increased by 30%±4% and 48%±3%, respectively, following clofibrate treatment. In addition, PPARα protein expression and PPARα activity were significantly lower in SHR than that in WKY rats. Clofibrate treatment significantly increased PPARα protein expression and PPARα activity in SHR rats, but not in WKY rats. Moreover, the vasoconstrictor response of aortic ring was markedly increased in SHRs, which was blunted after clofibrate treatment. Conclusion: PPARα contributes to regulation of blood pressure and vascular reactivity in SHR, and clofibrate-mediated reduction in blood pressure and proteinuria is probably through increased NO production.

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“…16 PPARa is also well known as a determinant of the development of hypertension and renal damage, especially in AT-II-induced hypertensive rats. 21,23,24,30 Induction of the renal expression of CYP4A enzymes in the kidney using fibrate compounds has been reported to lower BP in SHR, stroke-prone SHR and Dahl salt-sensitive rats. 31,32 We found the inverse pattern of PPARa expression in kidneys of WKY-HF rats compared with that in SHR-HF animals.…”

Section: Discussionmentioning

confidence: 99%

“…It does so through NO production, oxidative stress and cytochrome P450-derived eicosanoids in the kidney. 23,24 Therefore, in this study, we investigated the role of fenofibrate on renal lipotoxicity associated with hypertension and renal inflammation using spontaneously hypertensive (SHR) rats fed a high-fat (HF) diet.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

et al. 2009

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We investigated the effects of a high-fat (HF) diet and peroxisome proliferator-activated receptor (PPAR)-a activation on the intrarenal lipotoxicity associated with the renin-angiotensin system (RAS) and oxidative stress using spontaneously hypertensive (SHR) rats. Male SHR and Wistar-Kyoto (WKY) rats at 8 weeks of age were fed either a normal-fat diet or an HF diet without or with fenofibrate treatment for 12 weeks. Severe intrarenal lipid accumulation was noted in the SHR rats fed an HF diet than in WYK rats fed an HF diet (Po0.05). This lipid accumulation was associated with a 70% decrease in renal PPARa expression in SHR rats, whereas an HF diet increased the expression of PPARa in WKY rats by threefold. An HF diet also activated intrarenal, not systemic, RAS and induced oxidative stress associated with reduced nitric oxide (NO) bioavailability. By contrast, fenofibrate attenuated weight gain, fat mass and insulin resistance. Fenofibrate recovered HF diet-induced decreases in intrarenal PPARa expression and fat accumulation, and abolished intrarenal RAS activation and oxidative stress in SHR-HF animals (Po0.01). These activities conferred protection against increased blood pressure (BP), glomerulosclerosis and renal inflammation. Keywords: obesity; oxidative stress; PPARa; renal inflammation; renin-angiotensin system INTRODUCTION Currently, the prevalence of hypertension and chronic renal disease continues to increase among obese individuals. 1,2 It has been suggested that the development and progression of hypertension in an obese patient induces the activation of the systemic renin-angiotensin system (RAS) and the sympathetic nervous system. 3,4 In addition, it increases asymmetric dimethylarginine concentrations and vascular tone created by the reduced bioavailability of nitric oxide (NO) owing to increased oxidative stress. 5,6 Recent reports have demonstrated that it is not the systemic but the local (tissue specific) RAS activation that causes hypertension and renal damage 7-9 associated with local oxidative stress. [10][11][12] It has been shown that oxidative stress in kidneys of diabetic animals, measured by the electron spin resonance imaging technique, 10 high-performance liquid chromatography 13 and immunohistochemistry, 14 can be ameliorated by RAS inhibition.

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Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

Cited by 49 publications

References 34 publications

Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function

Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function

PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

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