Co-administration of the flavanol (-)-epicatechin with doxycycline synergistically reduces infarct size in a model of ischemia reperfusion injury by inhibition of mitochondrial swelling

Pilar Ortiz-Vilchis, Katrina Go Yamazaki, Ivan Rubio-Gayosso, Israel Ramirez-Sanchez, Claudia Calzada, Diego Romero-Perez, Alicia Ortiz, Eduardo Meaney, Pam Taub, Francisco Villarreal, Guillermo Ceballos

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)76-82
Number of pages7
JournalEuropean Journal of Pharmacology
Volume744
DOIs
StatePublished - 24 Feb 2015

Keywords

  • Doxycycline
  • Epicatechin
  • Ischemia-reperfusion
  • Mitochondrial swelling

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