P2X4 receptor-eNOS signaling pathway in cardiac myocytes as a novel protective mechanism in heart failure

Computational and Structural Biotechnology Journal
Ronghua YangBruce T Liang

Abstract

We have demonstrated using immunoprecipitation and immunostaining a novel physical association of the P2X4 receptor (P2X4R), a ligand-gated ion channel, with the cardioprotective, calcium-dependent enzyme endothelial nitric oxide synthase (eNOS). Treatment of murine ventricular myocytes with the P2XR agonist 2-methylthioATP (2-meSATP) to induce a current (mainly Na(+)) increased the formation of nitric oxide (NO), as measured using a fluorescent probe. Possible candidates for downstream effectors mediating eNOS activity include cyclic GMP and PKG or cellular protein nitrosylation. A cardiac-specific P2X4R overexpressing mouse line was protected from heart failure (HF) with improved cardiac function and survival in post-infarct, pressure overload, and calsequestrin (CSQ) overexpression models of HF. Although the role of the P2X4R in other tissues such as the endothelium and monocytes awaits characterization in tissue-specific KO, cardiac-specific activation of eNOS may be more cardioprotective than an increased activity of global systemic eNOS. The intra-myocyte formation of NO may be more advantageous over NO derived externally from a donor. A small molecule drug stimulating this sarcolemmal pathway or gene therapy-mediated ove...Continue Reading

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Citations

Feb 23, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sang Jun HanH Thomas Lee
Jun 2, 2020·Frontiers in Pharmacology·Leanne StokesElizabeth Allum
Feb 4, 2021·International Journal of Molecular Sciences·Muhammad AslamRainer Schulz

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