Abstract
Vaspin is an adipocytokine recently identified in the visceral adipose tissue of diabetic rats and having anti-diabetic effects. We have recently shown that vaspin has anti-atherogenic effect through Akt-mediated inhibition of endothelial cell apoptosis. Decreased activity of endothelial nitric oxide synthase (eNOS) plays an important role in the pathogenesis of atherosclerosis. Asymmetric dimethylarginine (ADMA) is a well-known endogenous competitive inhibitor of eNOS and risk factor of cardiovascular diseases. The aim of this study was to examine whether vaspin might protect against atherosclerosis through its beneficial effects on the ADMA-eNOS system. Treatment of vaspin significantly increased NO secretion from endothelial cells and isolated aorta from Sprague-Dawley (SD) rats. Furthermore, treatment of vaspin prevented fatty acid-induced decrease in endothelium-dependent vasorelaxation in isolated aorta of SD rat. For the mechanism of vaspin-induced NO biosynthesis, vaspin activated the STAT3 signaling pathway and stimulated eNOS phosphorylation (Ser 1177), a marker of eNOS activation, through STAT3-dependent mechanism. Furthermore, vaspin treatment increased the expression of dimethylarginine dimethylaminohydrolase (DDAH) II, the responsible enzyme for the degradation of ADMA, leading to a reduction in ADMA levels. Vaspin-induced increase in DDAH II gene expression was through STAT3-mediated stimulation of DDAH II promoter activity. These results suggest that vaspin increases eNOS activity by reducing ADMA level through STAT3-mediated regulation of DDAH II expression. Our findings provide a novel molecular mechanism of antiatherogenic actions of vaspin.
Highlights
Nitric oxide (NO) synthesized by endothelial nitric oxide synthase plays a crucial role in the maintenance of vascular tone and structure [1]
To investigate whether vaspin had an effect on the level of NO through the regulation of endothelial nitric oxide synthase (eNOS) activity, we first evaluated the effect of vaspin on the protein expression levels of total and phosphorylated-eNOS in HAECs
We investigated the effects of vaspin on eNOS activity and NO bioavailability and examined whether STAT3/dimethylarginine dimethylaminohydrolase (DDAH)/Asymmetric dimethylarginine (ADMA) system was involved in that action of vaspin
Summary
Nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) plays a crucial role in the maintenance of vascular tone and structure [1]. Decreased NO bioavailability is one of the major features of cardiovascular diseases (CVD) [2]. An impairment of endothelium-dependent vasorelaxation is present in atherosclerotic vessels even before vascular structural changes occur and represents the reduced eNOS-derived NO bioavailability [3]. Endothelial dysfunction characterized by an impairment of endothelium dependent vasorelaxation, and thereby reduced eNOS-derived NO bioactivity, is the critical step for atherogenesis [3]. ADMA has been shown to be a cardiovascular risk factor for numerous diseases [5] and elevated ADMA levels have been shown to attenuate endothelium-dependent vasodilation in humans [6]. The ADMADDAH system can be a target for treating CVD through the regulation of endogenous NO bioavailability
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