411-P: PRMT1 Upregulation and ADMA Accumulation Contribute to the High Sensitivity of Zucker Diabetic Fatty Rats to Myocardial Ischemia/Reperfusion Injury

Diabetic patients show a high sensitivity to myocardial ischemia/reperfusion (I/R) injury, but the underlying mechanism has remained obscure. Increasing evidence indicates that protein arginine methyltransferase1 (PRMT1) is implicated in modulation of cellular processes including gene transcription, energy metabolism, apoptosis and generation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS). ADMA as an intermediate of protein arginine methylation catalyzed by PRMT1 is associated with diabetic cardiovascular complications. This study was to examine whether PRMT1-ADMA disorder is involved in the high sensitivity to myocardial I/R injury in Zucker diabetic fatty (ZDF) rats. Myocardial I/R injury was induced by 30min of ligation in left anterior descending coronary artery followed by 2∼24h reperfusion. Cardiac function was measured by M-echocardiography, and ADMA signaling pathway was evaluated by expressions, activities or contents of signal molecules. ZDF rats showed severer cardiac dysfunction and larger area of infarction after myocardial I/R injury compared with Zucker-control rats. Expression and activity of PRMT1 and ADMA content were higher while expression and activity of NOS and nitric oxide (NO) content were lower in ZDF rats. Treatment with PRMT1 inhibitor TC-E or knockdown of PRMT1 with shRNA-PRMT1-LV reduced myocardial ADMA accumulation and protected cardiac function of ZDF rats from I/R injury. Exogenous ADMA perfusion of isolated heart from control rats could induce similar cardiac dysfunction to that of I/R injury. Treatment with TC-E or NO donor protected the isolated heart from I/R injury or ADMA-induced impairment. These results indicate that PRMT1 upregulation and ADMA accumulation contribute to the high sensitivity of ZDF rats to myocardial I/R injury and reveal the novel target for prevention and treatment of myocardial I/R injury in diabetes mellitus.