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C1q/TNF-related Proteins, A Family of Novel Adipokines, Induce Vascular Relaxation through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway
Arteriosclerosis, Thrombosis, and Vascular Biology (2011)
  • Qijung Zheng, 4th Military Medical University
  • Yuexing Yuan, 4th Military Medical University
  • Wei Yi, Thomas Jefferson University
  • Wayne Bond Lau, Thomas Jefferson University
  • Yajing Wang, Thomas Jefferson University
  • Xiaoliang Wang, Thomas Jefferson University
  • Yang Sun, Thomas Jefferson University
  • Bernard L. Lopez, Thomas Jefferson University
  • Theodore A. Christopher, Thomas Jefferson University
  • Jonathan M. Peterson, The Johns Hopkins University School of Medicine
  • G. William Wong, The Johns Hopkins University School of Medicine
  • Shiqiang Yu, 4th Military Medical University
  • Dinghua Yi, 4th Military Medical University
  • Xin-Liang Ma, Thomas Jefferson University
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 human umbilical vein endothelial cells. Of 8 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 on CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1, but not receptor 2, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, preincubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxative effects.

Conclusion
We have provided the first evidence that CTRP9 is a novel vasorelaxative adipocytokine that may exert vasculoprotective effects via the adiponectin receptor 1/AMPK/eNOS dependent/NO mediated signaling pathway.
Keywords
  • diabetes mellitus,
  • endothelial function,
  • nitric oxide,
  • signal transduction
Publication Date
October 19, 2011
DOI
10.1161/ATVBAHA.111.231050
Citation Information
Qijung Zheng, Yuexing Yuan, Wei Yi, Wayne Bond Lau, et al.. "C1q/TNF-related Proteins, A Family of Novel Adipokines, Induce Vascular Relaxation through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway" Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 31 Iss. 11 (2011) p. 2616 - 2623 ISSN: 1524-4636
Available at: http://works.bepress.com/jonathan-peterson/10/