title: Intravenous (-)-epicatechin reduces myocardial ischemic injury by protecting mitochondrial function.
abstract: 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.
  
  
  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 1h 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.
authors.affiliation: California State University Los Angeles, Department of Biological Sciences, Los Angeles, CA, United States; University of California San Diego, United States. Electronic address: Katrina.Yamazaki@calstatela.edu.
authors.forename: Katrina Go
authors.initials: KG
authors.lastname: Yamazaki
authors.affiliation: Department of Pharmacology, La Jolla, CA, United States.
authors.forename: Aleksander Y
authors.initials: AY
authors.lastname: Andreyev
authors.affiliation: Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ortiz-Vilchis
authors.affiliation: Department of Pharmacology, La Jolla, CA, United States.
authors.forename: Susanna
authors.initials: S
authors.lastname: Petrosyan
authors.affiliation: Department of Pharmacology, La Jolla, CA, United States.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Divakaruni
authors.affiliation: Department of Pharmacology, La Jolla, CA, United States.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Wiley
authors.affiliation: California State University Los Angeles, Department of Biological Sciences, Los Angeles, CA, United States; University of California San Diego, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: De La Fuente
authors.affiliation: National Center for Microscopy and Imaging Research, La Jolla, CA, United States.
authors.forename: Guy
authors.initials: G
authors.lastname: Perkins
authors.affiliation: Department of Medicine, La Jolla, CA, United States; Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ceballos
authors.affiliation: Department of Medicine, La Jolla, CA, United States.
authors.forename: Francisco
authors.initials: F
authors.lastname: Villarreal
authors.affiliation: Department of Pharmacology, La Jolla, CA, United States.
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D002392:Catechin / Q000008:administration & dosage*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002316:Cardiotonic Agents; D002392:Catechin
keywords: Cardiac metabolism; Epicatechin; Mitochondrial Ca(2+); Mitochondrial pyruvate carrier; Myocardial ischemia–reperfusion injury