TY - JOUR
T1 - Intravenous (-)-epicatechin reduces myocardial ischemic injury by protecting mitochondrial function
AU - Yamazaki, Katrina Go
AU - Andreyev, Aleksander Y.
AU - Ortiz-Vilchis, Pilar
AU - Petrosyan, Susanna
AU - Divakaruni, Ajit S.
AU - Wiley, Sandra E.
AU - De La Fuente, Christine
AU - Perkins, Guy
AU - Ceballos, Guillermo
AU - Villarreal, Francisco
AU - Murphy, Anne N.
N1 - Funding Information:
Funding sources : The authors are grateful to Dr. Joan Heller Brown's laboratory for provision of the neonatal rat ventricular myocytes (PO1 HL085577). This work was supported by NIH HL43617 , AT4277 , MD000220 to Dr. Villarreal, and DK92154 to Dr. Villarreal and Murphy and Conacyt Mexico # 129889 to Dr. Ceballos. Funding for Christine De La Fuente was provided from the National Institutes of Health Minority Access to Research Careers-Undergraduate Student Training for Academic Research Grant (NIH MARC U*STAR GM08228 ). Part of the work was performed at the National Center for Microscopy and Imaging Research funded by NIH P41GM103412-24 .
PY - 2014/8/1
Y1 - 2014/8/1
N2 - Background Targeting the mitochondria during ischemia/reperfusion (IR) can confer cardioprotection leading to improved clinical outcomes. The cardioprotective potential of (-)-epicatechin (EPI) during IR via modulation of mitochondrial function was evaluated. Methods and results Ischemia was induced in rats via a 45 min occlusion of the left anterior descending coronary artery followed by 1 h, 48 h, or 3 week reperfusion. EPI (10 mg/kg) was administered IV 15 min prior to reperfusion for the single dose group and again 12 h later for the double dose group. Controls received water. Experiments also utilized cultured neonatal rat ventricular myocytes (NRVM) and myoblasts. A single dose of EPI reduced infarct size by 27% at 48 h and 28% at 3 week. Double dose treatment further decreased infarct size by 80% at 48 h, and 52% by 3 weeks. The protective effect of EPI on mitochondrial function was evident after 1 h of reperfusion when mitochondria demonstrated less respiratory inhibition, lower mitochondrial Ca2 + load, and a preserved pool of NADH that correlated with higher tissue ATP levels. Mechanistic studies in NRVM revealed that EPI acutely stimulated maximal rates of respiration, an effect that was blocked by inhibitors of the mitochondrial pyruvate carrier, nitric oxide synthase, or soluble guanylyl cyclase. In myoblasts, knockdown of components of the mitochondrial pyruvate carrier blocked EPI-induced respiratory stimulation. Conclusions IV EPI confers cardioprotection via preservation of mitochondrial function potentially through enhanced substrate provision. These provocative results document a novel mechanism of a natural product with potential clinical utility.
AB - Background Targeting the mitochondria during ischemia/reperfusion (IR) can confer cardioprotection leading to improved clinical outcomes. The cardioprotective potential of (-)-epicatechin (EPI) during IR via modulation of mitochondrial function was evaluated. Methods and results Ischemia was induced in rats via a 45 min occlusion of the left anterior descending coronary artery followed by 1 h, 48 h, or 3 week reperfusion. EPI (10 mg/kg) was administered IV 15 min prior to reperfusion for the single dose group and again 12 h later for the double dose group. Controls received water. Experiments also utilized cultured neonatal rat ventricular myocytes (NRVM) and myoblasts. A single dose of EPI reduced infarct size by 27% at 48 h and 28% at 3 week. Double dose treatment further decreased infarct size by 80% at 48 h, and 52% by 3 weeks. The protective effect of EPI on mitochondrial function was evident after 1 h of reperfusion when mitochondria demonstrated less respiratory inhibition, lower mitochondrial Ca2 + load, and a preserved pool of NADH that correlated with higher tissue ATP levels. Mechanistic studies in NRVM revealed that EPI acutely stimulated maximal rates of respiration, an effect that was blocked by inhibitors of the mitochondrial pyruvate carrier, nitric oxide synthase, or soluble guanylyl cyclase. In myoblasts, knockdown of components of the mitochondrial pyruvate carrier blocked EPI-induced respiratory stimulation. Conclusions IV EPI confers cardioprotection via preservation of mitochondrial function potentially through enhanced substrate provision. These provocative results document a novel mechanism of a natural product with potential clinical utility.
KW - Cardiac metabolism
KW - Epicatechin
KW - Mitochondrial pyruvate carrier
KW - Myocardial ischemia-reperfusion injury
UR - http://www.scopus.com/inward/record.url?scp=84904254220&partnerID=8YFLogxK
U2 - 10.1016/j.ijcard.2014.05.009
DO - 10.1016/j.ijcard.2014.05.009
M3 - Artículo
C2 - 24908200
SN - 0167-5273
VL - 175
SP - 297
EP - 306
JO - International Journal of Cardiology
JF - International Journal of Cardiology
IS - 2
ER -