Fenofibrate treatment enhances antioxidant status and attenuates endothelial dysfunction in streptozotocin-induced diabetic rats

Abstract

Diabetic endothelial dysfunction is accompanied by increased oxidative stress and upregulated proinflammatory and inflammatory mediators in the vasculature. Activation of peroxisome proliferator-activated receptor-alpha (PPAR-α) results in antioxidant and anti-inflammatory effects. This study was designed to investigate the effect of fenofibrate, a PPAR-α activator, on the endothelial dysfunction, oxidative stress, and inflammation in streptozotocin diabetic rats. Diabetic rats received fenofibrate (150 mg kg(-1) day(-1)) for 4 weeks. Fenofibrate treatment restored the impaired endothelium-dependent relaxation and increased basal nitric oxide availability in diabetic aorta, enhanced erythrocyte/liver superoxide dismutase and catalase levels, ameliorated the abnormal serum/aortic thiobarbituric acid reactive substances, and prevented the increased aortic myeloperoxidase without a significant change in serum total cholesterol and triglyceride levels. It did not affect the decreased total homocysteine level and the increased tumor necrosis factor-α level in the serum of diabetic rats. Fenofibrate-induced prevention of the endothelial function seems to be related to its potential antioxidant and antiinflammatory activity.

Figure 1

Concentration-dependent contraction to phenylephrine (PE) in endothelium-intact [E(+)] (a) and endothelium-denuded [E(−)] (b) aortic rings and contractions induced by a single concentration of KCl (120 mM) (c) in endothelium-denuded aortic rings. C: control; D: diabetes mellitus; FF: fenofibrate. *P < .05 versus C; ^# P < .05 versus D.

Figure 2

Relaxant responses to acetylcholine (ACh) (a), calcium ionophore A23187 (b), L-arginine (c) and sodium nitroprusside (SNP) (d) in the endothelium-intact aortic rings of control (C), and diabetic (D) rats treated with/without fenofibrate (FF). Values are mean ± SEM of data obtained from 10 rats in each group. *P < .05 versus C.

Figure 3

Contractile responses to NG-Nitro-L-arginine methyl ester (L-NAME) (100 μM) in the endothelium-intact rings of control (C), and diabetic (D) rats treated with/without fenofibrate (FF). Responses were evaluated by calculating the ratio of additional contractions induced by L-NAME to the precontraction elicited by phenylephrine given at median effective concentration (EC₅₀). The contractile responses obtained by L-NAME indicate the production of nitric oxide as a product of basal endothelial NO synthase activity. Values are mean ± SEM of data obtained from 10 rats in each group. *P < .05 versus C; ^# P < .05 versus D.