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 $beta$3 adrenergic-receptor ($beta$3AR) 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 $beta$3AR 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 $beta$3AR agonist BRL37344 (5 $mu$g/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 $beta$3AR agonist-treated mice. Incubation with $beta$3AR agonist (BRL37344, 7 $mu$mol/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 $mu$g/kg) decreased infarct size and improved long-term LV contractile function. A single-dose administration of $beta$3AR 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:
$beta$3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes. (García-Prieto, Jaime, García-Ruiz, José Manuel, Sanz-Rosa, David, Pun, Andrés, García-Álvarez, Ana, Davidson, Sean M, Fernández-Friera, Leticia, Nuño-Ayala, Mario, Fernández-Jiménez, Rodrigo, Bernal, Juan A, Izquierdo-Garcia, José Luis, Jimenez-Borreguero, Jesús, Pizarro, Gonzalo, Ruiz-Cabello, Jesus, Macaya, Carlos, Fuster, Valentin, Yellon, Derek M and Ibáñez, Borja), In Basic research in cardiology, Springer Berlin Heidelberg, volume 109, 2014.
Bibtex Entry:
@article{GarciaPrieto:2014foe,
author = {Garc{'i}a-Prieto, Jaime and Garc{'i}a-Ruiz, Jos{'e} Manuel and Sanz-Rosa, David and Pun, Andr{'e}s and Garc{'i}a-{'A}lvarez, Ana and Davidson, Sean M and Fern{'a}ndez-Friera, Leticia and Nu{~n}o-Ayala, Mario and Fern{'a}ndez-Jim{'e}nez, Rodrigo and Bernal, Juan A and Izquierdo-Garcia, Jos{'e} Luis and Jimenez-Borreguero, Jes{'u}s and Pizarro, Gonzalo and Ruiz-Cabello, Jesus and Macaya, Carlos and Fuster, Valentin and Yellon, Derek M and Ib{'a}{~n}ez, Borja},
title = {{$beta$3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes.}},
journal = {Basic research in cardiology},
year = {2014},
volume = {109},
number = {4},
pages = {422},
month = jul,
publisher = {Springer Berlin Heidelberg},
affiliation = {Imaging, Epidemiology and Atherothrombosis Department, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fern{'a}ndez Almagro 3, 28029, Madrid, Spain.},
doi = {10.1007/s00395-014-0422-0},
pmid = {24951958},
language = {English},
rating = {0},
date-added = {2018-03-16T12:39:23GMT},
date-modified = {2020-07-09T13:27:49GMT},
abstract = {Selective stimulation of $beta$3 adrenergic-receptor ($beta$3AR) 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 $beta$3AR 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 $beta$3AR agonist BRL37344 (5~$mu$g/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 $beta$3AR agonist-treated mice. Incubation with $beta$3AR agonist (BRL37344, 7~$mu$mol/L) significantly reduced cell death in isolated adult mouse cardiomyocytes during hypoxia/reoxygenation and decreased susceptibility to deleterious opening of the mitochondrial permeability transition pore (mPTP), via a mechanism dependent on the Akt-NO signaling pathway. Pre-reperfusion BRL37344 administration had no effect on infarct size in cyclophilin-D KO mice, further implicating mPTP in the mechanism of protection. Large-white pigs underwent percutaneous coronary ischemia/reperfusion and 3-T CMR at 7 and 45~days post-infarction. Pre-perfusion administration of BRL37344 (5~$mu$g/kg) decreased infarct size and improved long-term LV contractile function. A single-dose administration of $beta$3AR 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.},
url = {http://link.springer.com/10.1007/s00395-014-0422-0},
uri = {url{papers3://publication/doi/10.1007/s00395-014-0422-0}}
}