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01-07-2014 | Original Contribution

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

Authors: 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

Published in: Basic Research in Cardiology | Issue 4/2014

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.

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Title: β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes
Authors: 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
Publication date: 01-07-2014
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 4/2014
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-014-0422-0

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

Abstract

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Abstract

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