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

• Published in: Computational and structural biotechnology journal 2015-01, Vol.13 (C), p.1-7
• Main Authors: Yang, Ronghua, Beqiri, Dardan, Shen, Jian-Bing, Redden, John M, Dodge-Kafka, Kimberly, Jacobson, Kenneth A, Liang, Bruce T
• Format: Article
• Language: English
• Subjects: Cardiac myocyte; Cardioprotection; Heart failure; Mini Review; Purines
• ISSN: 2001-0370; 2001-0370
• DOI: 10.1016/j.csbj.2014.11.002

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 overexpression of the P2X4R in cardiac myocytes may represent a new therapy for both ischemic and pressure overloaded HF.