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.


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.
Sala-Mercado
Javier A
JA
Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Wider
Joseph
J
Undyala
Vishnu Vardhan Reddy
VV
Jahania
Salik
S
Yoo
Wonsuk
W
Mentzer
Robert M
RM
Gottlieb
Roberta A
RA
Przyklenk
Karin
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002701:Chloramphenicol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019468:Disease Management; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D013552:Swine
D000900:Anti-Bacterial Agents; D051017:Apoptosis Regulatory Proteins; D002316:Cardiotonic Agents; D008869:Microtubule-Associated Proteins; D002701:Chloramphenicol; C026016:chloramphenicol succinate