by García-Prieto, Jaime, García-Ruiz, José Manuel, Sanz-Rosa, David, Pun, Andrés, García-Álvarez, Ana, Davidson, Sean M, Fernández-Friera, Leticia, Nuño-Ayala, Mario, Fernández-Jiménez, Rodrigo, Bernal, Juan A, Izquierdo-Garcia, José Luis, Jimenez-Borreguero, Jesús, Pizarro, Gonzalo, Ruiz-Cabello, Jesus, Macaya, Carlos, Fuster, Valentin, Yellon, Derek M and Ibáñez, Borja
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.
Reference:
β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes. (García-Prieto, Jaime, García-Ruiz, José Manuel, Sanz-Rosa, David, Pun, Andrés, García-Álvarez, Ana, Davidson, Sean M, Fernández-Friera, Leticia, Nuño-Ayala, Mario, Fernández-Jiménez, Rodrigo, Bernal, Juan A, Izquierdo-Garcia, José Luis, Jimenez-Borreguero, Jesús, Pizarro, Gonzalo, Ruiz-Cabello, Jesus, Macaya, Carlos, Fuster, Valentin, Yellon, Derek M and Ibáñez, Borja), In Basic research in cardiology, volume 109, 2014.
Bibtex Entry:
@article{garcia-prieto_3_2014,
	title = {β3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of {mPTP} opening in cardiomyocytes.},
	volume = {109},
	url = {http://link.springer.com/10.1007/s00395-014-0422-0},
	doi = {10.1007/s00395-014-0422-0},
	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.},
	language = {English},
	number = {4},
	journal = {Basic research in cardiology},
	author = {García-Prieto, Jaime and García-Ruiz, José Manuel and Sanz-Rosa, David and Pun, Andrés and García-Álvarez, Ana and Davidson, Sean M and Fernández-Friera, Leticia and Nuño-Ayala, Mario and Fernández-Jiménez, Rodrigo and Bernal, Juan A and Izquierdo-Garcia, José Luis and Jimenez-Borreguero, Jesús and Pizarro, Gonzalo and Ruiz-Cabello, Jesus and Macaya, Carlos and Fuster, Valentin and Yellon, Derek M and Ibáñez, Borja},
	month = jul,
	year = {2014},
	pmid = {24951958},
	note = {Publisher: Springer Berlin Heidelberg},
	pages = {422}
}