title: Activation of Sonic hedgehog signaling in ventricular cardiomyocytes exerts cardioprotection against ischemia reperfusion injuries.
abstract: Sonic hedgehog (SHH) is a conserved protein involved in embryonic tissue patterning and development. SHH signaling has been reported as a cardio-protective pathway via muscle repair-associated angiogenesis. The goal of this study was to investigate the role of SHH signaling pathway in the adult myocardium in physiological situation and after ischemia-reperfusion. We show in a rat model of ischemia-reperfusion that stimulation of SHH pathway, either by a recombinant peptide or shed membranes microparticles harboring SHH ligand, prior to reperfusion reduces both infarct size and subsequent arrhythmias by preventing ventricular repolarization abnormalities. We further demonstrate in healthy animals a reduction of QTc interval mediated by NO/cGMP pathway leading to the shortening of ventricular cardiomyocytes action potential duration due to the activation of an inward rectifying potassium current sharing pharmacological and electrophysiological properties with ATP-dependent potassium current. Besides its effect on both angiogenesis and endothelial dysfunction we demonstrate here a novel cardio-protective effect of SHH acting directly on the cardiomyocytes. This emphasizes the pleotropic effect of SHH pathway as a potential cardiac therapeutic target.
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Ludovit
authors.initials: L
authors.lastname: Paulis
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fauconnier
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Thireau
authors.affiliation: INSERM U1063, Stress oxydant et pathologies métaboliques, LUNAM Université, Angers, France.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Soleti
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Bastien
authors.initials: B
authors.lastname: Vidal
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Ouillé
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Bartholome
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Bideaux
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: François
authors.initials: F
authors.lastname: Roubille
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Guennec
authors.affiliation: INSERM U1063, Stress oxydant et pathologies métaboliques, LUNAM Université, Angers, France.
authors.forename: Ramaroson
authors.initials: R
authors.lastname: Andriantsitohaina
authors.affiliation: INSERM U1063, Stress oxydant et pathologies métaboliques, LUNAM Université, Angers, France.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Martínez
authors.affiliation: UMR CNRS 9214, Inserm U1046, Université de Montpellier, CHRU Montpellier, Montpellier, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; C546888:Shh protein, rat; D009569:Nitric Oxide; D006152:Cyclic GMP