Peroxisome Proliferator-Activated Receptor-α and Receptor-γ Activators Prevent Cardiac Fibrosis in Mineralocorticoid-Dependent Hypertension

Iglarz, Marc; Touyz, Rhian M.; Viel, Émilie C.; Paradis, Pierre; Amiri, Farhad; Diep, Quy N.; Schiffrin, Ernesto L.

doi:10.1161/01.hyp.0000083511.91817.b1

Cited by 142 publications

(105 citation statements)

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“…This promotes normalization of collagen turnover 10,18 and contributes, in part, to the improved LV structure and maintenance of normal LV function seen with fenofibrate. These findings complement previous reports that fenofibrate inhibits myocardial fibrosis and inflammation by inhibiting p38, 26,43 nuclear factor-B signaling pathways, 44 suppressing prohypertrophic and redox-regulated transcription factors, 28,31 cardiac endothelin-1 production, 26,45,46 and inhibiting MMP-9. 16 Additionally, both PPAR-␣ and PPAR-␥ agonists inhibit TGF-␤ signaling by interacting with Smad transcription factors [47][48][49] and although speculative, may constitute a mechanism for PPAR-␣-mediated inhibition of TGF-␤-regulated gene expression in aldosterone-induced fibrosis.…”

Section: Discussionsupporting

confidence: 91%

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

et al. 2007

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Abstract-Hypertension and cardiac remodeling are associated with myocardial fibrosis, left ventricular (LV) hypertrophy, and diastolic heart failure. Fenofibrate suppresses aldosterone-mediated increases in myocyte matrix metalloproteinase activity and extracellular signal-regulated kinase phosphorylation. It is unknown whether the peroxisome proliferatoractivated receptor-␣ agonist, fenofibrate, improves cardiac remodeling in a model of aldosterone-induced hypertension and LV hypertrophy. Twelve-week-old uninephrectomized FVB mice received 1% NaCl drinking water. Miniosmotic pumps delivered saline or aldosterone for 4 weeks. Mice were either untreated (nϭ14) or treated with fenofibrate 100 mg/kg per day (nϭ12) for 1 week before and 4 weeks after surgery. Key Words: fibrosis Ⅲ aldosterone Ⅲ hypertension Ⅲ cardiac remodeling Ⅲ matrix metalloproteinases Ⅲ peroxisome proliferator-activated receptor-␣ D iastolic heart failure (HF) refers to "HF with preserved left ventricular (LV) ejection fraction" 1-3 and is observed in almost half of the patients who present with clinical HF. 2 Hypertension, a significant risk factor for diastolic dysfunction and HF, 4 is frequently associated with cardiac remodeling and LV hypertrophy (LVH). 5 Similarly, LVH and diastolic dysfunction are associated with matrix metalloproteinase (MMP) activation that favors decreased extracellular matrix degradation and increased interstitial collagen, 6 thus perpetuating fibrosis. Tissue inhibitors of metalloproteinases (TIMPs) may predict HF in chronic hypertension. 7 Likewise, aldosterone antagonists (used in chronic HF and in hypertension) exert positive effects by downregulating MMP activity. 8 -11 Despite the increasing incidence of diastolic HF and elevated mortality rates, 12 there remains a paucity of therapies that target these potential underlying mechanism(s).Fenofibrate, a peroxisome proliferator-activated receptor-␣ (PPAR-␣) agonist, is used clinically for the treatment of dyslipidemias. Intriguingly, fibrates are being considered as possible therapeutic agents for the treatment of cardiac remodeling. 13 The myocardial effects of fenofibrate are independent of its lipid-lowering actions and are partly due to PPAR-␣-mediated suppression of inflammatory transcription factors (eg, nuclear factor-B and activating protein-1) 14 -16 and inhibition of macrophage recruitment. 17 Inhibition of nuclear factor-B with fenofibrates in hypertension prevents the development of diastolic dysfunction. 18 We previously demonstrated in isolated adult cardiomyocytes that fenofibrate

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Section: Discussionsupporting

confidence: 91%

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

et al. 2007

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“…PPAR␣ expression is increased in blood vessels of spontaneously hypertensive rats (22), and fenofibrate lowers blood pressure in these rats (11,23). Fenofibrate also prevents cardiac fibrosis in mineralocorticoid-dependent hypertensive rats (24). C-reactive protein upregulates AT 1 R in vascular smooth muscle cells, and these effects are attenuated by losartan (25).…”

Section: Effects Of Therapies On Adiponectin and Insulin Resistancementioning

confidence: 99%

Additive Beneficial Effects of Fenofibrate Combined With Candesartan in the Treatment of Hypertriglyceridemic Hypertensive Patients

et al. 2006

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OBJECTIVE -Mechanisms underlying fibric acid and angiotensin II type 1 receptor blocker therapies differ. Signaling from peroxisome proliferator-activated receptor ␣ may cross-talk with the angiotensin II system. We investigated vascular and metabolic responses to these therapies either alone or in combination in hypertriglyceridemic hypertensive patients.RESEARCH DESIGN AND METHODS -This was a randomized, double-blind, placebo-controlled, cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Forty-four patients were given 200 mg fenofibrate and placebo, 200 mg fenofibrate and 16 mg candesartan, or 16 mg candesartan and placebo daily during each treatment period.RESULTS -Fenofibrate, combined therapy, or candesartan therapy significantly reduced blood pressure. However, combined therapy significantly reduced blood pressure more than fenofibrate or candesartan alone (P Ͻ 0.001 by ANOVA). When compared with candesartan, fenofibrate or combined therapy significantly improved the lipoprotein profile. All three treatment arms significantly improved flow-mediated dilator response to hyperemia. Combined therapy significantly decreased plasma malondialdehyde, high-sensitivity C-reactive protein, and soluble CD40L levels relative to baseline measurements. Importantly, these parameters were changed to a greater extent with combined therapy when compared with monotherapy (P Ͻ 0.001, P ϭ 0.002, P ϭ 0.050, and P ϭ 0.032 by ANOVA, respectively). Fenofibrate, combined therapy, and candesartan significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements. However, the magnitude of these increases were not significantly different among the three therapies (P ϭ 0.246 and P ϭ 0.153 by ANOVA, respectively).CONCLUSIONS -Fenofibrate combined with candesartan improves endothelial function and reduces inflammatory markers to a greater extent than monotherapy in hypertriglyceridemic hypertensive patients. Diabetes Care 29:195-201, 2006H ypertriglyceridemia and hypertension are major public health problems that are frequently treated with fenofibrate and angiotensin II type 1 receptor (AT 1 R) blockers (ARBs), respectively. Although the mechanisms of action for these two classes of drugs differ, both classes have beneficial effects on the vasculature. Large-scale clinical studies have demonstrated that micronized fenofibrate, fibric acid, and losartan, an ARB, prevent and retard the progression of coronary heart disease (1,2). Hypertension and coronary heart disease are frequently associated with insulin resistance and disorders of metabolic homeostasis such as obesity and type 2 diabetes. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance and the pathophysiology of diabetes and its vascular complications (3). Indeed, large-scale clinical studies have demonstrated that candesartan reduces the onset of type 2 diabetes (4). The mechanisms of this benefit may relate to the ability of these therapies t...

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“…Extracts of Shiliuhua had been previously reported to activate PPAR and induce PPAR expression. We found that ethanolic extract of Shiliuhua significantly activated both PPAR and PPAR, which might account for its anti-fibrotic activity since agonists of PPAR (Toyama et al, 2004;Iglarz et al, 2003) and PPAR (Milam et al, 2008;Kawai et al, 2008;Iglarz et al, 2003) were previously reported to suppress fibrosis of liver, lung, heart and kidney. Contrary to our hypothesis, we found that the antifibrotic activities of Shiliuhua extract can only be partially blocked by GW6471, a PPAR antagonist, at a dose 42-fold of its reported IC 50 .…”

Section: Shiliuhua and Pparmentioning

confidence: 61%

Knowledge-Based Discovery of Anti-Fibrotic and Pro-Fibrotic Activities from Chinese Materia Medica

Xu¹,

Wong²,

Qu³

et al. 2012

Recent Advances in Theories and Practice of Chinese Medicine

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Peroxisome Proliferator-Activated Receptor-α and Receptor-γ Activators Prevent Cardiac Fibrosis in Mineralocorticoid-Dependent Hypertension

Cited by 142 publications

References 42 publications

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

Additive Beneficial Effects of Fenofibrate Combined With Candesartan in the Treatment of Hypertriglyceridemic Hypertensive Patients

Knowledge-Based Discovery of Anti-Fibrotic and Pro-Fibrotic Activities from Chinese Materia Medica

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