title: Co-administration of the flavanol (-)-epicatechin with doxycycline synergistically reduces infarct size in a model of ischemia reperfusion injury by inhibition of mitochondrial swelling.
abstract: (-)-Epicatechin (EPI) is cardioprotective in the setting of ischemia/reperfusion (IR) injury and doxycycline (DOX) is known to preserve cardiac structure/function after myocardial infarction (MI). The main objective of this study was to examine the effects of EPI and DOX co-administration on MI size after IR injury and to determine if cardioprotection may involve the mitigation of mitochondrial swelling. For this purpose, a rat model of IR was used. Animals were subjected to a temporary 45 min occlusion of the left anterior descending coronary artery. Treatment consisted of a single or double dose of EPI (10 mg/kg) combined with DOX (5 mg/kg). The first dose was given 15 min prior to reperfusion and the second 12 h post-MI. The effects of EPI +/- DOX on mitochondrial swelling (i.e. mPTP opening) were determined using isolated mitochondria exposed to calcium overload and data examined using isobolographic analysis. To ascertain for the specificity of EPI effects on mitochondrial swelling other flavonoids were also evaluated. Single dose treatment reduced MI size by ~46% at 48 h and 44% at three weeks. Double dosing evidenced a synergistic, 82% reduction at 3 weeks. EPI plus DOX also inhibited mitochondrial swelling in a synergic manner thus, possibly accounting for the cardioprotective effects whereas limited efficacy was observed with the other flavonoids. Given the apparent lack of toxicity in humans, the combination of EPI and DOX may have clinical potential for the treatment of myocardial IR injury.
authors.affiliation: Escuela Superior de Medicina del Instituto Politecnico Nacional, Seccion de Posgrado, Mexico City, Mexico.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ortiz-Vilchis
authors.affiliation: University of California, San Diego, Department of Medicine, San Diego, CA, USA.
authors.forename: Katrina Go
authors.initials: KG
authors.lastname: Yamazaki
authors.affiliation: Escuela Superior de Medicina del Instituto Politecnico Nacional, Seccion de Posgrado, Mexico City, Mexico.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rubio-Gayosso
authors.affiliation: Escuela Superior de Medicina del Instituto Politecnico Nacional, Seccion de Posgrado, Mexico City, Mexico.
authors.forename: Israel
authors.initials: I
authors.lastname: Ramirez-Sanchez
authors.affiliation: Escuela Superior de Medicina del Instituto Politecnico Nacional, Seccion de Posgrado, Mexico City, Mexico.
authors.forename: Claudia
authors.initials: C
authors.lastname: Calzada
authors.affiliation: Universidad Autonoma de Baja California, Mexico.
authors.forename: Diego
authors.initials: D
authors.lastname: Romero-Perez
authors.affiliation: Escuela Nacional de Ciencias Biologicas del Instituto Politecnico Nacional, Mexico.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Escuela Superior de Medicina del Instituto Politecnico Nacional, Seccion de Posgrado, Mexico City, Mexico.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Meaney
authors.affiliation: University of California, San Diego, Department of Medicine, San Diego, CA, USA.
authors.forename: Pam
authors.initials: P
authors.lastname: Taub
authors.affiliation: University of California, San Diego, Department of Medicine, San Diego, CA, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Villarreal
authors.affiliation: Escuela Superior de Medicina del Instituto Politecnico Nacional, Seccion de Posgrado, Mexico City, Mexico. Electronic address: gceballosr@ipn.mx.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ceballos
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002392:Catechin / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology*; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects; D008933:Mitochondrial Swelling / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy*
chemical_list: D002316:Cardiotonic Agents; D005419:Flavonoids; D002392:Catechin; D004318:Doxycycline
keywords: Doxycycline; Epicatechin; Ischemia-reperfusion; Mitochondrial swelling