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Am J Physiol Heart Circ Physiol (January 8, 2004). doi:10.1152/ajpheart.00935.2003
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Submitted on October 1, 2003
Accepted on January 5, 2004

Differential Contribution of Necrosis and Apoptosis in Myocardial Ischemia/Reperfusion Injury

James D. McCully1*, Hidetaka Wakiyama1, Yng-Ju Hsieh1, Mara Jones1, and Sidney Levitsky1

1 Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Havard Medical School, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: james_mccully{at}hms.harvard.edu.

Necrosis and apoptosis differentially contribute to myocardial injury. Determination of the contribution of these processes in ischemia/reperfusion injury would allow for the preservation of myocardial tissue. Necrosis and apoptosis were investigated in Langendorff perfused rabbit hearts (n=47) subjected to 0, 5, 10, 15, 20, 25, 30 min. global ischemia (GI-) and 120 min reperfusion. Myocardial injury was determined by TTC staining, TUNEL, bax, bcl2, PARP cleavage, caspase -3,-8,-9 cleavage and activity, Fas-ligand (FasL) and Fas activated death domain (FADD). The contribution of apoptosis was determined separately (n=42) using irreversible caspase-3,-8,-9 inhibitors. RESULTS: LVPDP and systolic shortening (SS) were significantly decreased and infarct size and TUNEL positive cells were significantly increased (p<0.05 vs. Control) at GI-20, GI-25 and GI-30. Pro-apoptotic bax, PARP cleavage and caspase- 3,-9 cleavage and activity were apparent at GI 5 to GI-30. Fas, FADD, caspase-8 cleavage and activity were unaltered. Irreversible inhibition of caspase-3,-9 activity significantly decreased (p<0.05) infarct size at GI-25 and GI-30 but had no effect on LVPDP or SS. CONCLUSION: Myocardial injury results from a significant increase in both necrosis and apoptosis (p<0.05 vs. Control) evident by TUNEL, TTC staining and caspase activity at GI-20. Intrinsic pro-apoptotic activation is evident early during ischemia but does not significantly contribute to infarct size prior to GI-25. The contribution of necrosis to infarct size at GI-20, GI-25 and GI-30 is significantly greater than that of apoptosis. Apoptosis is significantly decreased by caspase inhibition during early reperfusion but this protection does not improve immediate post-ischemic functional recovery.




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