C1q/TNF-Related Proteins, A Family of Novel Adipokines, Induce Vascular Relaxation Through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway

Abstract

Objective Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction. However, APN knockout animals manifest modest systemic dysfunction unless metabolically challenged. The protein family CTRPs (C1q/TNF-related proteins) has recently been identified as APN paralogs and some CTRP members share APN’s metabolic regulatory function. However, the vasoactive properties of CTRPs remain completely unknown. Methods and Results The vasoactivity of currently identified murine CTRP members was assessed in aortic vascular rings and underlying molecular mechanisms was elucidated in HUVECs. Of eight CTRPs, CTRPs 3, 5, and 9 caused significant vasorelaxation. The vasoactive potency of CTRP9 exceeded that of APN (3-fold), and is endothelium-dependent and nitric oxide (NO) mediated. Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased 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, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, pre-incubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxive effects. Conclusion We have provided the first evidence that CTRP9 is a novel vasorelaxive adipocytokine which may exert vasculoprotective effects via the AdipoR1/AMPK/eNOS dependent/NO mediated signaling pathway.

Adipose tissue-derived cytokines, CTRPs as biomarkers and therapeutic targets in metabolism and the cardiovascular system

“…Adiponectin, as an insulin sensitizer, assembles with CTRP9 to form heterotrimers [12] , by which CTRP9 and adiponectin share the same receptor to exert their cardiovascular protective function [13] . In addition to forming the homo-oligomers, CTRP6/ CTRP1, CTRP7/CTRP2, and CTRP2/adiponectin form heterotrimers generating functionally distinct ligands to provide new framework for the action of this family of secreted glycoproteins in normal and diseases states [11] .…”

“…Clinic studies indicate close association between CTRPs levels and CVDs. Conversely, the expression of inflammatory mediators in human tissues has been observed to be inversely regulated related to the levels of CTRPs [13,39] . Hence, the reciprocal relationship among CTRPs and the inflammatory mediators may present a dynamic crosstalk in the development of obesity and diabetic complications.…”

AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases

“…A fat-derived plasma protein, C1q/TNF-related protein 9 (CTRP9), has shown benefi cial effect on glucose metabolism ( 177 ) and vascular function ( 178 ). Decreased levels of CTRP9 have been observed in mouse model of ischemia-reperfusion injury and in DIO mice ( 179 ).…”

Cardiovascular and Metabolic Regulation by the Adiponectin/C1q/Tumor Necrosis Factor–Related Protein Family of Proteins

“…12 It has also been shown that CTRP9 can influence endothelial function via an AMPK-dependent mechanism. 13 Another report has shown that administration of CTRP9 attenuates cardiac injury after ischemia/reperfusion through modulation of AMPK signaling. 14 CTRP5 has been shown to promote AMPK signaling in cultured myotubes, thereby leading to increased glucose uptake.…”