title: Novel protective role of endogenous cardiac myocyte P2X4 receptors in heart failure.
abstract: BACKGROUND
  Heart failure (HF), despite continuing progress, remains a leading cause of mortality and morbidity. P2X4 receptors (P2X4R) have emerged as potentially important molecules in regulating cardiac function and as potential targets for HF therapy. Transgenic P2X4R overexpression can protect against HF, but this does not explain the role of native cardiac P2X4R. Our goal is to define the physiological role of endogenous cardiac myocyte P2X4R under basal conditions and during HF induced by myocardial infarction or pressure overload.
  
  
  RESULTS
  Mice established with conditional cardiac-specific P2X4R knockout were subjected to left anterior descending coronary artery ligation-induced postinfarct or transverse aorta constriction-induced pressure overload HF. Knockout cardiac myocytes did not show P2X4R by immunoblotting or by any response to the P2X4R-specific allosteric enhancer ivermectin. Knockout hearts showed normal basal cardiac function but depressed contractile performance in postinfarct and pressure overload models of HF by in vivo echocardiography and ex vivo isolated working heart parameters. P2X4R coimmunoprecipitated and colocalized with nitric oxide synthase 3 (eNOS) in wild-type cardiac myocytes. Mice with cardiac-specific P2X4R overexpression had increased S-nitrosylation, cyclic GMP, NO formation, and were protected from postinfarct and pressure overload HF. Inhibitor of eNOS, L-N(5)-(1-iminoethyl)ornithine hydrochloride, blocked the salutary effect of cardiac P2X4R overexpression in postinfarct and pressure overload HF as did eNOS knockout.
  
  
  CONCLUSIONS
  This study establishes a new protective role for endogenous cardiac myocyte P2X4R in HF and is the first to demonstrate a physical interaction between the myocyte receptor and eNOS, a mediator of HF protection.
authors.affiliation: From Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT (T.Y., J.S., R.Y., J.R., K.D.-K., J.G., B.T.L.); and Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD (K.A.J.).
authors.forename: Tiehong
authors.initials: T
authors.lastname: Yang
authors.affiliation: From Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT (T.Y., J.S., R.Y., J.R., K.D.-K., J.G., B.T.L.); and Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD (K.A.J.).
authors.forename: Jian-bing
authors.initials: JB
authors.lastname: Shen
authors.affiliation: From Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT (T.Y., J.S., R.Y., J.R., K.D.-K., J.G., B.T.L.); and Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD (K.A.J.).
authors.forename: Ronghua
authors.initials: R
authors.lastname: Yang
authors.affiliation: From Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT (T.Y., J.S., R.Y., J.R., K.D.-K., J.G., B.T.L.); and Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD (K.A.J.).
authors.forename: John
authors.initials: J
authors.lastname: Redden
authors.affiliation: From Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT (T.Y., J.S., R.Y., J.R., K.D.-K., J.G., B.T.L.); and Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD (K.A.J.).
authors.forename: Kimberly
authors.initials: K
authors.lastname: Dodge-Kafka
authors.affiliation: From Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT (T.Y., J.S., R.Y., J.R., K.D.-K., J.G., B.T.L.); and Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD (K.A.J.).
authors.forename: James
authors.initials: J
authors.lastname: Grady
authors.affiliation: From Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT (T.Y., J.S., R.Y., J.R., K.D.-K., J.G., B.T.L.); and Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD (K.A.J.).
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: From Pat and Jim Calhoun Cardiology Center, University of Connecticut Medical Center, Farmington, CT (T.Y., J.S., R.Y., J.R., K.D.-K., J.G., B.T.L.); and Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD (K.A.J.). bliang@uchc.edu.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Liang
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000517:prevention & control*; D008026:Ligation / Q000009:adverse effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000150:complications* / Q000209:etiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D058848:Receptors, Purinergic P2X4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D058848:Receptors, Purinergic P2X4; D052250:Nitric Oxide Synthase Type III
keywords: heart failure; myocytes, cardiac; purines