Growing attention has been given to the role of the Rho kinase pathway in the development of heart disease and ischemia/reperfusion (I/R) injury. Y-27632 is a Rho kinase inhibitor demonstrated to protect against I/R injury, but the exact mechanism by which it does so remains to be elucidated. The goal of this project was to determine new targets by which Y-27632 can protect the heart against I/R injury. Isolated rat hearts were perfused under aerobic conditions or subjected to I/R in the presence or absence of Y-27632. Administration of Y-27632 (1 μM) before ischemia and during the first 10 min of reperfusion resulted in complete recovery of cardiac function. 2-D electrophoresis followed by MS identified four proteins whose levels were affected by Y-27632 treatment. Lactate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase were significantly increased in the Y-27632 treated group, while creatine kinase was normalized to control levels. In addition, we found increased level of two different molecular fragments of ATP synthase, which were normalized by Y-27632. This increase suggests that during ischemia ATP synthase is subjected to degradation. The changes in metabolic enzymes' levels and their regulation by Y-27632 suggest that the cardioprotective effect of Y-27632 involves increased energy production.
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