TY - JOUR
T1 - β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes
AU - García-Prieto, Jaime
AU - García-Ruiz, Jose Manuel
AU - Sanz-Rosa, David
AU - Pun, Andrés
AU - García-Alvarez, Ana
AU - Davidson, Sean M.
AU - Fernández-Friera, Leticia
AU - Nuno-Ayala, Mario
AU - Fernández-Jiménez, Rodrigo
AU - Bernal, Juan A.
AU - Izquierdo-Garcia, José Luis
AU - Jimenez-Borreguero, Jesús
AU - Pizarro, Gonzalo
AU - Ruiz-Cabello, Jesús
AU - Macaya, Carlos
AU - Fuster, Valentín
AU - Yellon, Derek M.
AU - Ibanez, Borja
N1 - Funding Information:
D.S-R is supported by a CNIC-Postdoctoral Fellowship; JM.G-R and A.G-A were supported by CNIC-Cardiojoven Fellowships. The “Red de Investigación Cardiovascular (RIC)” of the Spanish Ministry of Health supports B.I (RD 12/0042/0054) and A.G-A. The “Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)” is supported by the Spanish Ministry of Economy and Competitiveness, and the Pro-CNIC Foundation.
Funding Information:
This work was supported by an award from the Fondo de Investigación Sanitaria to BI a (FIS 10/02268) and by the competitive grant “CNIC translational 01/2009”, also to BI.
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
KW - Beta-adrenergic receptor blocker
KW - Ischemia/reperfusion
KW - Magnetic resonance imaging
KW - Mitochondrial permeability transition pore
KW - Myocardial infarction
UR - https://www.scopus.com/pages/publications/84902714796
U2 - 10.1007/s00395-014-0422-0
DO - 10.1007/s00395-014-0422-0
M3 - Article
C2 - 24951958
AN - SCOPUS:84902714796
SN - 0300-8428
VL - 109
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 4
M1 - 422
ER -