Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1

Li-Chieh Ching, Yu Ru Kou, Song-Kun Shyue, Kuo-Hui Su, Jeng Wei, Li-Ching Cheng, Yuan-Bin Yu, Ching-Chian Pan, Tzong-Shyuan Lee
Cardiovascular Research 2011 August 1, 91 (3): 492-501

AIMS: We investigated the molecular mechanism underlying the role of transient receptor potential vanilloid type 1 (TRPV1), a Ca(2+)-permeable non-selective cation channel, in the activation of endothelial nitric oxide (NO) synthase (eNOS) in endothelial cells (ECs) and mice.

METHODS AND RESULTS: In ECs, TRPV1 ligands (evodiamine or capsaicin) promoted NO production, eNOS phosphorylation, and the formation of a TRPV1-eNOS complex, which were all abrogated by the TRPV1 antagonist capsazepine. TRPV1 ligands promoted the phosphorylation of Akt, calmodulin-dependent protein kinase II (CaMKII) and TRPV1, and increased the formation of a TRPV1-Akt-CaMKII complex. Removal of extracellular Ca(2+) abolished the ligand-induced increase in the phosphorylation of Akt and CaMKII, formation of a TRPV1-eNOS complex, and eNOS activation. Inhibition of PI3K and CaMKII suppressed the ligand-induced increase in TRPV1 phosphorylation, formation of a TRPV1-eNOS complex, and eNOS activation. TRPV1 activation increased the phosphorylation of Akt, CaMKII, and eNOS in the aortas of wild-type mice but failed to activate eNOS in TRPV1-deficient aortas. Additionally, TRPV1 ligand-induced angiogenesis was diminished in eNOS- or TRPV1-deficient mice. When compared with apolipoprotein E (ApoE)-deficient mice, ApoE/TRPV1-double-knockout mice displayed reduced phosphorylation of eNOS, Akt, and CaMKII in aortas but worsened atherosclerotic lesions.

CONCLUSION: TRPV1 activation in ECs may trigger Ca(2+)-dependent PI3K/Akt/CaMKII signalling, which leads to enhanced phosphorylation of TRPV1, increased TRPV1-eNOS complex formation, eNOS activation and, ultimately, NO production.

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