PPAR-α effects on the heart and other vascular tissues

Francis, Gordon A.; Annicotte, Jean-Sébastien; Auwerx, Johan

doi:10.1152/ajpheart.01118.2002

Cited by 84 publications

(72 citation statements)

References 105 publications

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“…PPAR␣, the main isoform in the adult heart, 11 is downregulated in PO hypertrophy, 12 and its dysregulation is associated with cardiac dysfunction. 13 Conversely, PPAR␣ ligands reduce cardiac hypertrophy and inflammation 14,15 and, in acute PO, attenuate cardiac fibrosis. 9 Finally, mice lacking PPAR␣ are reportedly resistant to pleiotropic actions of PPAR␣ ligands.…”

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confidence: 99%

Peroxisome Proliferator-Activated Receptor α–Independent Actions of Fenofibrate Exacerbates Left Ventricular Dilation and Fibrosis in Chronic Pressure Overload

et al. 2007

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Abstract-Progressive cardiac remodeling is characterized by subsequent chamber hypertrophy, enlargement, and pump dysfunction. It is also associated with increased cardiac fibrosis and matrix turnover. Interestingly, peroxisome proliferator-activated receptor (PPAR) ␣ activators reduce cardiac hypertrophy, inflammation, and fibrosis. Little is known about the role of fenofibrates in mediating PPAR␣-independent effects in response to chronic pressure overload (PO). Wild-type and PPAR␣-deficient mice were subjected to chronic PO caused by ascending aortic constriction to test the role of fenofibrates in chronic, progressive cardiac remodeling by a PPAR␣-independent mechanism. Mice were randomized to regular chow or chow-containing fenofibrate (100 mg/kg of body weight per day) for 1 week before and 8 weeks after ascending aortic constriction. In the presence of PPAR␣, wild-type chronic PO mice, treated with fenofibrate, had improved cardiac remodeling. However, PO PPAR␣-deficient mice treated with fenofibrate had increased mortality, significantly adverse left ventricular end diastolic (3.4Ϯ0.1 versus 4.2Ϯ0.1 mm) and end systolic (1.5Ϯ0.2 versus 2.5Ϯ0.2 mm) dimensions, and fractional shortening (57Ϯ3% versus 40Ϯ3%). Fenofibrate also increased myocardial hypertrophy, cardiac fibrosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2 in PO PPAR␣-deficient mice. Fenofibrate inhibited matrix metalloproteinase activity in vitro and aldosterone-induced increases in extracellular signal-regulated kinase phosphorylation. Thus, fenofibrate improved cardiac remodeling in chronic PO mice. However, in PPAR␣-deficient mice, this chronic PO was exacerbated and associated with increased myocardial fibrosis and altered matrix remodeling. In the absence of PPAR␣, fenofibrates exerts deleterious, pleiotropic myocardial actions. This is an important observation, because PPAR␣ agonists are considered possible inhibitory regulators of cardiac remodeling in the remodeled heart. (Hypertension. 2007; 49:1084-1094.)

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confidence: 99%

Peroxisome Proliferator-Activated Receptor α–Independent Actions of Fenofibrate Exacerbates Left Ventricular Dilation and Fibrosis in Chronic Pressure Overload

et al. 2007

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“…Recent reports demonstrate that altered fatty acid metabolism is associated with cardiomyopathy and nephropathy (8,9). Accumulation of excess lipids in nonadipose tissues leads to cell dysfunction or cell death (8,9).…”

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confidence: 99%

“…This phenomenon, known as lipotoxicity, may play an important role in the pathogenesis of diabetes and heart failure in humans (8). Several mechanisms have been suggested to underlie lipotoxicity, including a direct toxic effect of fatty acids or products of their metabolism, increased production of reactive oxygen species, ATP deficiency, and fatty acidinduced apoptosis (8,9).…”

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confidence: 99%

Accelerated Diabetic Nephropathy in Mice Lacking the Peroxisome Proliferator–Activated Receptor α

Park

Kim²,

Ko³

et al. 2006

Diabetes

128

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Peroxisome proliferator-activated receptor (PPAR)␣, a member of the ligand-activated nuclear receptor superfamily, plays an important role in lipid metabolism and glucose homeostasis and is highly expressed in the kidney. The present studies were aimed at determining the role of PPAR␣ in the pathogenesis of diabetic nephropathy using PPAR␣-knockout mice and cultured murine mesangial cells. Diabetes was induced using a low-dose streptozotocin protocol in 8-week-old male 129 SvJ PPAR␣-knockout and wild-type mice. Diabetic PPAR␣-knockout and wildtype mice developed elevated fasting blood glucose (P < 0.001) and HbA 1c levels (P < 0.001). Renal functional and histopathological changes in diabetic and nondiabetic PPAR␣-knockout and wild-type mice were evaluated after 16 weeks of hyperglycemia. PPAR␣ immunostaining of the cortical tubules of diabetic wild-type mice was elevated by hyperglycemia. In diabetic PPAR␣-knockout mice, renal disease with accompanying albuminuria, glomerular sclerosis, and mesangial area expansion was more severe than in diabetic wild-type mice (P < 0.05) and was accompanied by increased levels of serum free fatty acids and triglycerides (P < 0.01). Furthermore, they exhibited increased renal immunostaining for type IV collagen and osteopontin, which was associated with increased macrophage infiltration and glomerular apoptosis. There were no significant differences in these indexes of renal disease between nondiabetic PPAR␣-knockout and wild-type mice and diabetic PPAR␣ wild-type mice. In vitro studies demonstrated that high glucose levels markedly increased the expression of type IV collagen, transforming growth factor-␤1, and the number of leukocytes adherent to cultured mesangial cells. Adherence of leukocytes was inhibited by the PPAR␣ agonist fenofibrate. Taken together, PPAR␣ deficiency appears to aggravate the severity of diabetic nephropathy through an increase in extracellular matrix formation, inflammation, and circulating free fatty acid and triglyceride concentrations. PPAR␣ agonists may serve as useful therapeutic agents for type 1 diabetic nephropathy. Diabetes 55: [885][886][887][888][889][890][891][892][893] 2006

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“…Peroxisome proliferator-activated receptor (PPAR) α is a member of the family of nuclear transcription factors that act as lipid sensors and regulate lipid metabolism [7][8][9]. A PPAR α activator, fenofibrate, is known to promote fatty acid oxidation and to lower circulating lipids, and has been used as a hypolipidemic drugs [10,11]. Several studies have examined the effects of fenofibrate on daily food intake, body weight, and lipid profile in rodent models of obesity.…”

Section: Introductionmentioning

confidence: 99%

Fenofibrate Reduces Age-related Hypercholesterolemia in Normal Rats on a Standard Diet

Han

Kim

et al. 2010

Korean J Physiol Pharmacol

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Plasma cholesterol is increased in normal aging in both rodents and humans. This is associated with reduced elimination of cholesterol and decreased receptor-mediated clearance of plasma low-density lipoprotein (LDL) cholesterol. The aims of this study were: (1) to determine age-related changes in plasma lipid profiles, and (2) to determine the effect of fenofibrate, an activator of peroxisome proliferator activated receptor alpha (PPAR α), on plasma lipid profiles in normal rats on a standard diet. Male Sprague-Dawley (SD) rats (n=15) were fed standard chow and water from 10 to 25 weeks of age. During that period, we measured daily food intake, body weight, fasting and random blood glucose levels, plasma total cholesterol (TC), triglycerides (TG), and free fatty acid (FFA) levels. At 20 weeks of age, all rats were randomly divided into two groups: a fenofibrate group (in which rats were gavaged with 300 mg/kg/day of fenofibrate) and a control group (gavaged with water). Fenofibrate treatment lasted 5 weeks. There were no significant changes in daily food intake, blood glucose, and plasma TG level with age. Body weight, plasma TC, and FFA levels were significantly increased with age. Fenofibrate significantly decreased plasma concentrations of TC and FFA, which had been increased with age. However, fenofibrate did not influence the plasma concentration of TG, which had not increased with age. These results suggest that fenofibrate might have a novel role in preventing age-related hypercholesterolemia in SD rats on a normal diet.

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PPAR-α effects on the heart and other vascular tissues

Cited by 84 publications

References 105 publications

Peroxisome Proliferator-Activated Receptor α–Independent Actions of Fenofibrate Exacerbates Left Ventricular Dilation and Fibrosis in Chronic Pressure Overload

Peroxisome Proliferator-Activated Receptor α–Independent Actions of Fenofibrate Exacerbates Left Ventricular Dilation and Fibrosis in Chronic Pressure Overload

Accelerated Diabetic Nephropathy in Mice Lacking the Peroxisome Proliferator–Activated Receptor α

Fenofibrate Reduces Age-related Hypercholesterolemia in Normal Rats on a Standard Diet

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