Abstract 1899: Inhibition of Contractile Activity during Ischemic Postconditioning Enhances Cardioprotection through RISK-Dependent Restoration of Sarcolemmal Dystrophin
Dystrophin plays a pivotal role in protection of the sarcolemma from physical stress-induced cardiomyocyte (CM) oncosis. Dystrophin is translocated during ischemia (I) but redistributed to the sarcolemma during reperfusion (R) depending on the recovery of mitochondrial function and cellular ATP level. Although ischemic postconditioning (IPost) prevents R injury by protecting mitochondria through activation of R injury salvage kinase (RISK), a potential drawback of IPost is delayed recovery of myocardial ATP by repeated I that may inhibit restoration of sarcolemmal dystrophin and increase CM oncosis during IPost. Therefore, we hypothesized that temporary inhibition of contractile activity during IPost enhances cardioprotection by preventing CM oncosis through RISK-dependent restoration of sarcolemmal dystrophin. Isolated rat hearts were subjected to 30 min I and 2 hr R. IPost induced by 20 cycles of 10 sec I and 10 sec R activated Akt, an essential member of RISK, and improved mitochondrial function of CM as evaluated by tetramethylrhodamine ethylester uptake. However, myocardial ATP and redistribution of dystrophin to the sarcolemma were not increased during IPost. This was associated with no inhibition of CM oncosis during IPost as evaluated by Evans blue uptake, although IPost significantly increased myocardial ATP and significantly reduced infarct size 2 hr after R. Inhibition of contractile activity during IPost by treatment with 2,3-butanedione monoxim (BDM) prevented CM oncosis during IPost and potentiated the infarct size-limiting effect of IPost without affecting the anti-apoptotic effect of IPost as evaluated by caspase-3 activity and TUNEL analysis. The phosphatidylinositol 3-kinase inhibitor LY294002 abolished activation of Akt, improvement of mitochondrial function, increase in myocardial ATP, restoration of sarcolemmal dystrophin, inhibition of CM oncosis during IPost in the presence of BDM and abrogated the infarct size-limiting and anti-apoptotic effects of IPost. These results suggest that temporary inhibition of contractile activity during IPost enhances cardioprotection by preventing CM oncosis through RISK-dependent restoration of sarcolemmal dystrophin.