Peroxisome proliferator-activated receptor alpha agonist, clofibrate, has profound influence on myocardial fatty acid composition

Abstract

The hypolipidemic fibrates have been identified as agonists of the peroxisome proliferator-activated receptor α (PPARα), which plays a critical role in the regulation of cardiac fatty acid metabolism. Despite the widespread clinical use of fibrates, their role in myocardial oxidative stress and fatty acid composition is less known. In this study, male Sprague–Dawley rats were treated with either vehicle (olive oil, 1 ml/kg) or clofibrate (300 mg/kg day i.p.) for 1–14 days. Lipid peroxidation in heart homogenate was determined by thiobarbituric acid reactive substance (TBARS) assay. Results show that hearts from clofibrate-treated rats are more susceptible to FeSO 4-induced TBARS production. The antioxidants including catalase and glutathione-related enzymes were marginally affected. We demonstrated that myocardial fatty acid composition was dramatically altered by clofibrate treatment. In hearts from clofibrate-treated rats, the principal n − 6 polyunsaturated fatty acids (PUFAs), linoleic acid (C18:2 n − 6) and arachidonic acid (C20:4 n − 6), was significantly reduced, while the content of the principal n − 3 PUFA, docosahexaenoic acid (C22:6 n − 3), was markedly increased. The overall effect was to reduce n − 6/ n − 3 ratio and increase the unsaturation extent of myocardial fatty acids. Functional study showed that hearts from clofibrate-treated rats had an improved recovery of post-ischemic contractile function and reduced ischemia/reperfusion (I/R)-induced infarct size. The data shows that clofibrate has a profound impact on cardiac fatty acid composition, which may contribute to its cardioprotective effect.