Abstract 8966: C1q/TNF-Related Proteins (CTRPs), a Family of Novel Adipokines, Induce Vascular Relaxation through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway

Abstract

Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction and vascular injury. However, APN knockout animals manifest only modest systemic dysfunction unless metabolically challenged. The CTRP (C1q/TNF-related proteins) family has recently been identified as APN paralogs. Some CTRP members share APN’s metabolic regulatory function. However, the vascular biology of CTRPs remains completely unknown. This study assessed the vasoactivity of currently identified murine CTRP members utilizing in vitro and in vivo experimental models, and elucidated underlying molecular mechanisms in HUVECs. Of eight CTRPs investigated, three CTRPs (3, 5, and 9) caused significant vasorelaxation in concentration-dependent fashion, while the remaining CTRPs neither constricted nor dilated aortic segments. The vasodilatory potency of CTRP9 exceeded that of APN (3-fold), is endothelium-dependent, and mediated by nitric oxide (NO). Plasma CTRP9 levels were markedly increased in APN knockout mice, and significantly reduced in high-fat-diet induced obesity/diabetic mice (P<0.05). One week of in vivo CTRP9 administration initiated after 3 weeks high-fat-diet, at a dose restoring physiological CTRP9 levels, significantly improved vascular endothelial function (P<0.01). Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased endothelial NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect upon CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1 (AdipoR1), but not receptor 2 (AdipoR2), knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, pre-incubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasodilatory effects. Collectively, we have provided the first evidence that CTRP9 is a novel vasodilatory/vasculoprotective adipokine, potentially compensatory for APN’s vascular effects in APN knockout animals. Moreover, we have demonstrated that CTRP9 exerts its vascular biological effects via the AdipoR1/AMPK/eNOS dependent/NO mediated signaling pathway.