Abstract 21290: Adipose Tissue Factors and the Adipokine Resistin-Induce Vascular Endothelial Dysfunction via Arginase Upregulation

Abstract

Introduction: Obesity is a major contributor to cardiovascular disorders, for which endothelial cell (EC) dysfunction is a hallmark. Obesity-induced EC dysfunction has been linked to dysregulation of the visceral adipose tissue (VAT) resulting in increased secretion of the pro-inflammatory cytokine resistin and alterations in endothelial nitric oxide (NO) producing capacity. However, mechanisms underlying this pathology are not well understood. Hypothesis: Resistin impairs vascular EC function via upregulation of endothelial arginase1 (ARG1) expression and activity, thus limiting L-arginine availability for NO synthesis. Methods: To determine the effect of obesity on EC function, conditioned media prepared from VAT (VAT CM) of high fat diet-induced obese mice, VAT CM from lean mice or resistin (100 ηg/ml) were used to treat mouse aortic endothelial cells (MAEC) and aortic rings for 24 hr. Results: VAT CM from obese mice increased endothelial ARG1 mRNA by 34% and decreased NO level by 32% (p<0.05), vs VAT CM from lean mice. Aortic rings incubated with obese VAT CM markedly reduced endothelium-dependent vasorelaxation (EDV) to acetylcholine. Moreover, resistin levels were 143% higher in obese VAT CM compared to lean VAT CM. In MAEC, resistin increased ARG1 mRNA by 30% and decreased NO production by 39% (p<0.05). Co-treatment with the specific ARG inhibitor (ABH, 100 μM) or supplementing EC with L-arginine increased NO to near normal levels. Incubation of aortic rings with resistin also impaired EDV. This dysfunction was largely prevented by co-treatment with ABH or in aortic rings from EC specific-ARG1 knockout mice. The resistin-induced increase in ARG1 expression in MAEC is attributed to Toll-like receptor 4 (TLR4)-induced activation of p38 MAPK pathway as co-treatment with specific TLR4 inhibitor (CLI-095) inhibited p38 activation and ARG1 expression (34% and 33%, respectively, p<0.05) and increased NO production by 38% (p<0.05). Additionally, co-treatment with a specific p38 inhibitor prevented resistin-induced increase in endothelial ARG1 expression. Conclusions: VAT factors and particularly resistin induce vascular endothelial dysfunction via elevated arginase expression/activity. Support : NIH EY11766 & HL70215 & AHA fellowship