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Mol Med. 2012;18:805-15. doi: 10.2119/molmed.2011.00461.

Implication of AMP-activated protein kinase in transient receptor potential vanilloid type 1-mediated activation of endothelial nitric oxide synthase.

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1
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.

Abstract

We investigated whether AMP-activated protein kinase (AMPK), a multi-functional regulator of energy homeostasis, is involved in transient receptor potential vanilloid type 1 (TRPV1)-mediated activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) and mice. In ECs, treatment with evodiamine, the activator of TRPV1, increased the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and eNOS, as revealed by western blot analysis. Inhibition of AMPK activation by compound C or dominant-negative AMPK mutant abrogated the evodiamine-induced increase in phosphorylation of AMPK and eNOS and NO bioavailability, as well as tube formation in ECs. Immunoprecipitation and two-hybrid analysis demonstrated that AMPK mediated the evodiamine-induced increase in the formation of a TRPV1-eNOS complex. Additionally, TRPV1 activation by evodiamine increased the phosphorylation of AMPK and eNOS in aortas of wild-type mice but did not activate eNOS in aortas of TRPV1-deficient mice. In mice, inhibition of AMPK activation by compound C markedly decreased evodiamine-evoked angiogenesis in Matrigel plugs and in a hind-limb ischemia model. Moreover, evodiamine-induced phosphorylation of AMPK and eNOS in aortas of apolipoprotein E deficient (ApoE(-/-)) mice was abrogated in TRPV1-deficient ApoE(-/-) mice. In conclusion, TRPV1 activation may trigger AMPK-dependent signaling, which leads to enhanced activation of AMPK and eNOS and retarded development of atherosclerosis.

PMID:
22451268
DOI:
10.2119/molmed.2011.00461
[Indexed for MEDLINE]
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