P2X4 receptor-eNOS signaling pathway in cardiac myocytes as a novel protective mechanism in heart failure.
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.
Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT, United States.
Ronghua
R
Yang
Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT, United States.
Dardan
D
Beqiri
Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT, United States.
Jian-Bing
JB
Shen
Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT, United States.
John M
JM
Redden
Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT, United States.
Kimberly
K
Dodge-Kafka
Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD, United States.
Kenneth A
KA
Jacobson
Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT, United States.
Bruce T
BT
Liang
Cardiac myocyte; Cardioprotection; Heart failure; Purines