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

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.

Acute induction of autophagy as a novel strategy for cardioprotection: getting to the heart of the matter.

There is no question that necrosis and apoptosis contribute to cardiomyocyte death in the setting of myocardial ischemia-reperfusion. Indeed, considerable effort and resources have been invested in the development of novel therapies aimed at attenuating necrotic and apoptotic cell death, with the ultimate goal of applying these strategies to reduce infarct size and improve outcome in patients suffering acute myocardial infarction (MI) or 'heart attack'. However, an issue that remains controversial is the role of autophagy in determining the fate of ischemic-reperfused cardiomyocytes: i.e., is induction of autophagy detrimental or protective? Recent data from our group obtained in the clinically relevant, in vivo swine model of acute MI provides novel evidence of a positive association between pharmacological upregulation of autophagy (achieved by administration of chloramphenicol succinate (CAPS)) and increased resistance to myocardial ischemia-reperfusion injury.