Role of ceramide in ischemic preconditioning

BACKGROUND: A recent study showed increased myocardial content of ceramide and sphingosine during preconditioning (PC). Because sphingosine-1-phosphate, a metabolite of ceramide, may function as an antiapoptotic factor, we hypothesized the increased ceramide during PC may be heart's effort to harness its own protection. STUDY DESIGN: The isolated hearts were divided into five groups: 1) perfused for 3 hours 45 minutes with KHB buffer (control); 2) perfused with buffer for 45 minutes followed by 30 minutes of ischemia and 2 hours of reperfusion; 3) perfused for 15 minutes with desipramine followed by 30 minutes of perfusion with buffer, 30 minutes of ischemia, and 2 hours of reperfusion; 4) preconditioned followed by, 30 minutes of ischemia and 2 hours of reperfusion; and 5) the same as 4), but preperfused for 15 minutes with desipramine. Myocardial preservation was assessed by examining left ventricular function, infarct size, and cardiomyocyte apoptosis. RESULTS: Ischemia/reperfusion-mediated cardiac dysfunction was partially restored with desipramine. PC improved postischemic ventricular recovery and reduced myocardial infarct size and cardiomyocyte apoptosis. The cardioprotective abilities of PC were abolished with desipramine, which also downregulated a PC-mediated increase in antiapoptotic protein Bcl-2. The apparent paradoxical results of desipramine can be explained by the increase in proapoptotic ceramide content in the ischemic reperfused heart that was blocked with desipramine and an increase in antiapoptotic sphingosine-1-p content in the preconditioned heart that was inhibited with desipramine. CONCLUSIONS: The results suggested for the first time that sphingolipid can induce the expression of Bcl-2 warranting its clinical use as a pharmacologic PC agent. (J Am Coll Surg 2004;198: 770-777. (C) 2004 by the American College of Surgeons)