title: β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes.
abstract: Selective stimulation of β3 adrenergic-receptor (β3AR) has been shown to reduce infarct size in a mouse model of myocardial ischemia/reperfusion. However, its functional long-term effect and the cardioprotective mechanisms at the level of cardiomyocytes have not been elucidated, and the impact of β3AR stimulation has not been evaluated in a more translational large animal model. This study aimed at evaluating pre-perfusion administration of BRL37344 both in small and large animal models of myocardial ischemia/reperfusion. Pre-reperfusion administration of the β3AR agonist BRL37344 (5 μg/kg) reduced infarct size at 2-and 24-h reperfusion in wild-type mice. Long-term (12-weeks) left ventricular (LV) function assessed by echocardiography and cardiac magnetic resonance (CMR) was significantly improved in β3AR agonist-treated mice. Incubation with β3AR agonist (BRL37344, 7 μmol/L) significantly reduced cell death in isolated adult mouse cardiomyocytes during hypoxia/reoxygenation and decreased susceptibility to deleterious opening of the mitochondrial permeability transition pore (mPTP), via a mechanism dependent on the Akt-NO signaling pathway. Pre-reperfusion BRL37344 administration had no effect on infarct size in cyclophilin-D KO mice, further implicating mPTP in the mechanism of protection. Large-white pigs underwent percutaneous coronary ischemia/reperfusion and 3-T CMR at 7 and 45 days post-infarction. Pre-perfusion administration of BRL37344 (5 μg/kg) decreased infarct size and improved long-term LV contractile function. A single-dose administration of β3AR agonist before reperfusion decreased infarct size and resulted in a consistent and long-term improvement in cardiac function, both in small and large animal models of myocardial ischemia/reperfusion. This protection appears to be executed through inhibition of mPTP opening in cardiomyocytes.
authors.affiliation: Imaging, Epidemiology and Atherothrombosis Department, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: García-Prieto
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: García-Ruiz
authors.forename: David
authors.initials: D
authors.lastname: Sanz-Rosa
authors.forename: Andrés
authors.initials: A
authors.lastname: Pun
authors.forename: Ana
authors.initials: A
authors.lastname: García-Alvarez
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
authors.forename: Leticia
authors.initials: L
authors.lastname: Fernández-Friera
authors.forename: Mario
authors.initials: M
authors.lastname: Nuno-Ayala
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Fernández-Jiménez
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bernal
authors.forename: José Luis
authors.initials: JL
authors.lastname: Izquierdo-Garcia
authors.forename: Jesús
authors.initials: J
authors.lastname: Jimenez-Borreguero
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Pizarro
authors.forename: Jesús
authors.initials: J
authors.lastname: Ruiz-Cabello
authors.forename: Carlos
authors.initials: C
authors.lastname: Macaya
authors.forename: Valentín
authors.initials: V
authors.lastname: Fuster
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
authors.forename: Borja
authors.initials: B
authors.lastname: Ibanez
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D002316:Cardiotonic Agents; D000081406:Peptidyl-Prolyl Isomerase F; D004983:Ethanolamines; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D022702:Receptors, Adrenergic, beta-3; D009569:Nitric Oxide; C057368:BRL 37344; D051057:Proto-Oncogene Proteins c-akt; D021983:Cyclophilins