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

被引:65
作者
Garcia-Prieto, Jaime [1 ]
Manuel Garcia-Ruiz, Jose [1 ,2 ]
Sanz-Rosa, David [1 ]
Pun, Andres [1 ]
Garcia-Alvarez, Ana [1 ,3 ]
Davidson, Sean M. [4 ]
Fernandez-Friera, Leticia [1 ,5 ]
Nuno-Ayala, Mario [1 ]
Fernandez-Jimenez, Rodrigo [1 ]
Bernal, Juan A. [6 ]
Luis Izquierdo-Garcia, Jose [7 ,8 ,9 ]
Jimenez-Borreguero, Jesus [1 ]
Pizarro, Gonzalo [1 ,10 ]
Ruiz-Cabello, Jesus [7 ,8 ,9 ]
Macaya, Carlos [11 ]
Fuster, Valentin [1 ,12 ]
Yellon, Derek M. [4 ]
Ibanez, Borja [1 ,11 ]
机构
[1] Ctr Nacl Invest Cardiovasc Carlos III CNIC, Imaging Epidemiol & Atherothrombosis Dept, Madrid 28029, Spain
[2] Hosp Univ Cent Asturias, Oviedo, Spain
[3] Hosp Clin Barcelona, Barcelona, Spain
[4] UCL, Hatter Cardiovasc Inst, London, England
[5] Hosp Univ Monteprincipe, Madrid, Spain
[6] CNIC, Cardiovasc Dev & Repair Dept, Madrid, Spain
[7] CNIC, Adv Imaging Unit, Madrid, Spain
[8] Ciber Enfermedades Resp, Madrid, Spain
[9] Univ Complutense, E-28040 Madrid, Spain
[10] Hosp Univ Quiron, Madrid, Spain
[11] Hosp Clin San Carlos, Cardiovasc Inst, Madrid, Spain
[12] Mt Sinai Sch Med, Zena & Michael A Wiener CVI, New York, NY USA
关键词
beta(3) adrenergic receptor; Magnetic resonance imaging; Myocardial infarction; Beta-adrenergic receptor blocker; Ischemia/reperfusion; Mitochondrial permeability transition pore; MITOCHONDRIAL PERMEABILITY TRANSITION; ISCHEMIA-REPERFUSION INJURY; ACUTE MYOCARDIAL-INFARCTION; NITRIC-OXIDE; PORE; CARDIOPROTECTION; RISK; SIZE; BETA(3)-ADRENOCEPTOR; CYCLOSPORINE;
D O I
10.1007/s00395-014-0422-0
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页数:15
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