Angiotensin II II ‐preconditioning is associated with increased PKC PKC ε/ PKC PKC δ ratio and prosurvival kinases in mitochondria

摘要

Summary Angiotensin II ‐preconditioning ( APC ) has been shown to reproduce the cardioprotective effects of ischaemic preconditioning ( IPC ), however, the molecular mechanisms mediating the effects of APC remain unknown. In this study, Langendorff‐perfused rat hearts were subjected to IPC , APC or both ( IPC / APC ) followed by ischaemia‐reperfusion ( IR ), to determine translocation of PKC ε, PKC δ, Akt, Erk1/2, JNK , p38 MAPK and GSK ‐3β to mitochondria as an indicator of activation of the protein kinases. In agreement with previous observations, IPC , APC and IPC / APC increased the recovery of left ventricular developed pressure ( LVDP ), reduced infarct size ( IS ) and lactate dehydrogenase ( LDH ) release, compared to controls. These effects were associated with increased mitochondrial PKC ε/ PKC δ ratio, Akt, Erk1/2, JNK , and inhibition of permeability transition pore ( mPTP ) opening. Chelerythrine, a pan‐ PKC inhibitor, abolished the enhancements of PKC ε but increased PKC δ expression, and inhibited Akt, Erk1/2, and JNK protein levels. The drug had no effect on the APC ‐ and IPC / APC ‐induced cardioprotection as previously reported, but enhanced the post‐ischaemic LVDP in controls. Losartan, an angiotensin II type 1 receptor ( AT 1‐R) blocker, abolished the APC ‐stimulated increase of LVDP and reduced PKC ε, Akt, Erk1/2, JNK , and p38. Both drugs reduced ischaemic contracture and LDH release, and abolished the inhibition of mPTP by the preconditioning. Chelerythrine also prevented the reduction of IS by APC and IPC / APC . These results suggest that the cardioprotection induced by APC and IPC / APC involves an AT 1‐R‐dependent translocation of PKC ε and survival kinases to the mitochondria leading to mPTP inhibition. In chelerythrine‐treated hearts, however, alternate mechanisms appear to maintain cardiac function.