β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes

Jaime García-Prieto, Jose Manuel García-Ruiz, David Sanz-Rosa, Andrés Pun, Ana García-Alvarez, Sean M. Davidson, Leticia Fernández-Friera, Mario Nuno-Ayala, Rodrigo Fernández-Jiménez, Juan A. Bernal, José Luis Izquierdo-Garcia, Jesús Jimenez-Borreguero, Gonzalo Pizarro, Jesús Ruiz-Cabello, Carlos Macaya, Valentín Fuster, Derek M. Yellon, Borja Ibanez

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59 Scopus citations

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.

Original languageEnglish
Article number422
JournalBasic Research in Cardiology
Volume109
Issue number4
DOIs
StatePublished - Jul 2014

Keywords

  • Beta-adrenergic receptor blocker
  • Ischemia/reperfusion
  • Magnetic resonance imaging
  • Mitochondrial permeability transition pore
  • Myocardial infarction

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