Profound Cardioprotection With Chloramphenicol Succinate in the Swine Model of Myocardial Ischemia-Reperfusion Injury

• Published in: Circulation (New York, N.Y.) Vol. 122; no. 11; pp. S179 - S184
• Main Authors: SALA-MERCADO, Javier A, WIDER, Joseph, REDDY UNDYALA, Vishnu Vardhan, JAHANIA, Salik, YOO, Wonsuk, MENTZER, Robert M, GOTTLIEB, Roberta A, PRZYKLENK, Karin
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 14-09-2010
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Apoptosis Regulatory Proteins - metabolism; Autophagy - drug effects; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiotonic Agents - pharmacology; Cardiovascular system; Chloramphenicol - analogs & derivatives; Chloramphenicol - pharmacology; Disease Management; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Gene Expression Regulation - drug effects; Humans; Male; Medical sciences; 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; Pharmacology. Drug treatments; Swine; Vasodilator agents. Cerebral vasodilators; Myocardial infarction; autophagy; Ischemia reperfusion; Chloramphenicol; Myocardial ischemia; Cardiovascular disease; Coronary heart disease; Myocardial disease; ischemia; Vascular disease; Antibiotic; Reperfusion; Antibacterial agent
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.109.928242

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.
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.
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.