Abstract 18885: CTRP1, an Adipokine Causing Endothelial Dysfunction Through Upregulation of Arginase 1, is Associated With the Severity of Coronary Artery Disease in Patients and Promotes Atherogenesis in Mice

Abstract

Background: C1q/TNF-related protein (CTRP) 1 was initially identified as a paralog of adiponectin based on the similarity in C1q domain of these two proteins. However, vascular functions of CTRP1 remain largely undetermined. Here, we sought to investigate whether CTRP1 influences the pathogenesis of atherosclerosis. Methods and Results: We analyzed CTRP1 levels in sera of coronary artery disease (CAD) patients (n=451) and non-CAD controls (n=686), in coronary endarterectomy specimens (n=26) and non-atherosclerotic internal mammary arteries (n=32), and in peripheral blood mononuclear cells (PBMCs) from severe CAD patients (n=58) and non-CAD controls (n=25). CTRP1 levels were higher in sera, endarterectomy specimens and PBMCs from CAD patients compared with controls, and were related to CAD severity. Immunohistochemistry of human femoral arteries exhibited VE-cadherin loci-associated increased CTRP1 expression in atherosclerotic plaques. In cultured endothelial cells, CTRP1 stimulation resulted in reduced nitric oxide (NO) bioavailability and promotion of inflammatory reactions (increased production of inflammatory cytokines and induction of adhesion molecules). Intravital microscopy exhibited impaired endothelium-dependent arteriole dilation and enhanced leukocyte-endothelium interactions after injection of recombinant CTRP1, whereas improved arteriole dilation and decreased leukocyte-endothelium interactions were observed in CTRP1 knockout mice. Furthermore, we found that arginase 1 was significantly increased by CTRP1 in a dose-dependent fashion, thereby leading to eNOS-uncoupling and reactive oxygen species generation. Inhibition of arginase activity by synthetic chemicals markedly improved CTRP1-dependent endothelial dysfunction. Finally, intraperitoneal injection of recombinant CTRP1 promoted atherogenesis in apoE-/- mice. In contrast, proatherogenic effects were significantly attenuated in CTRP1-/-/apoE-/- double knockout mice. Conclusions: Our findings have demonstrated that CTRP1 is a pro-atherogenic adipokine, likely by modulating arginase 1 expression and enzyme activity. CTPP1 may represent a crucial therapeutic target in atherosclerosis.