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

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.

• Authors: Javier A Sala-Mercado, Joseph Wider, Vishnu Vardhan Reddy Undyala, Salik Jahania, Wonsuk Yoo, Robert M Mentzer Jr, Roberta A Gottlieb, Karin Przyklenk
• Journal: Circulation (Circulation) Vol. 122 Issue 11 Suppl Pg. S179-84 (Sep 14 2010) ISSN: 1524-4539 [Electronic] United States
• PMID: 20837911 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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