Abstract 15526: Apoptosis Signal Regulating Kinase-1 Inhibitor Decreases Mitochondrial Damage during Ischemia-Reperfusion
BACKGROUND: Apoptosis signal regulating kinase-1 (ASK1) is a MAPK kinase kinase activated by oxidative stress that directly regulates cell death through p38, JNK, and other effectors. A selective small molecule inhibitor of ASK1, (ASK1-i) given at reperfusion (REP) reduced in vivo infarct size measured at 24 hrs and 7 days. Damage to the mitochondrial electron transport chain (ETC) from ischemia (ISC) increases oxidant production and favors mitochondrial permeability transition (MPT) during REP. The role of mitochondria (MITO) in ASK1-i mediated protection was studied.
METHODS: Isolated, buffer perfused mouse hearts underwent: (1) Time control perfusion (2) Vehicle (0.025% DMSO) treated 25 min ISC and 30 min REP (3) ASK1-i (10 uM) given before ISC and during early REP (Drug+I/R) (4) early REP only (I+Drug+R). Lactate dehydrogenase (LDH) release was the index of cell death. MITO were isolated and oxidative-phosphorylation (OXPHOS) measured using glutamate or succinate + rotenone. MPT susceptibility (calcium retention capacity-CRC) was studied.
RESULTS: ISC-REP increased LDH release which was reduced in both ASK1-i treatment groups (Table). ISC-REP decreased OXPHOS with complex I substrate which was protected by ASK1-i treatment either before ISC or only at REP. ASK1-i treatment decreased susceptibility to MPT. Remarkably, treatment only during REP was as protective as treatment before ISC.
CONCLUSION: ASK1-i treatment during ISC-REP limits damage to MITO at complex I and increases resistance to MPT. Thus, treatment at the onset of REP with a cell-permeable small molecule inhibitor of ASK1 limits MITO-driven cardiac injury at REP as the likely mechanism of the sustained myocardial salvage previously observed in vivo in a preclinical model of STEMI treated by REP.
- © 2012 by American Heart Association, Inc.