P2X4 Receptor-eNOS Signaling Pathway in Cardiac Myocytes as a Novel Protective Mechanism in Heart Failure

Publication date: Available online 7 November 2014 Source:Computational and Structural Biotechnology Journal Author(s): Ronghua Yang , Dardan Beqiri , Jian-Bing Shen , John M. Redden , Kimberly Dodge-Kafka , Kenneth A. Jacobson , Bruce T. Liang 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 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 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 overexpres...
Source: Computational and Structural Biotechnology Journal - Category: Biotechnology Source Type: research