Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury

Circulation. 2010 Sep 14;122(11 Suppl):S179-84. doi: 10.1161/CIRCULATIONAHA.109.928242.

Abstract

Background: Emerging evidence suggests that "adaptive" induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction.

Methods and results: Anesthetized pigs underwent 45 minutes of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS) (an agent that purportedly upregulates autophagy; 20 mg/kg) or saline at 10 minutes before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 minutes following CAPS treatment and assayed (by immunoblotting) for 2 proteins involved in autophagosome formation: Beclin-1 and microtubule-associated protein light chain 3-II. To investigate whether the efficacy of CAPS was maintained with "delayed" treatment, additional pigs received CAPS (20 mg/kg) at 30 minutes after occlusion. Expression of Beclin-1 and microtubule-associated protein light chain 3-II, as well as infarct size, were assessed at end-reperfusion. CAPS was cardioprotective: infarct size was 25±5 and 41±4%, respectively, in the CAPS-pretreated and CAPS-delayed treatment groups versus 56±5% in saline controls (P<0.01 and P<0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins.

Conclusions: Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / drug effects
  • Cardiotonic Agents / pharmacology*
  • Chloramphenicol / analogs & derivatives*
  • Chloramphenicol / pharmacology
  • Disease Management
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Male
  • Microtubule-Associated Proteins / biosynthesis
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Infarction / prevention & control*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Swine

Substances

  • Anti-Bacterial Agents
  • Apoptosis Regulatory Proteins
  • Cardiotonic Agents
  • Microtubule-Associated Proteins
  • Chloramphenicol
  • chloramphenicol succinate