GW24-e3077 Inhibition of PICK1 has the Protective Effect on Adriamycin-induced Toxic Myocarditis

Objectives Adriamycin (ADR) has broad-spectrum effect such as anti-tumour and antibiotic, but it is limited the application for its dose-dependent cardiac toxicity. PICK1 is the interaction protein of PKC, which has been suggested as a potential drug target against brain ischaemia, pain and cocaine addiction. Our previous study has shown that the expression of PICK1 has increased in ADR-induced toxic myocarditis. In this study, the possible protect effect of FSC231, the specifical PDZ domain inhibitor of PICK1, against ADR-induced toxic myocarditis were carried out. Methods An experimental ADR-induced toxic myocarditis model was induced by intraperitoneal injection of ADR (3mg/kg) one day intervals on 14 consecutive days in mice. FSC231 (0.1ml/10g, 25 μM) was administrated by intraperitoneal injection on 14 consecutive days. At the end of the experiment, mice were sacrificed and their hearts were harvested for marker enzyme, histologic and molecular biologic analysis. The expression of PKCα and PICK1 were tested by Western blot. Results Results showed that the myocardial fibre necrosis and the higher of lactate dehydrogenase (LDH) in myocardium were found in ADR-induced toxic myocarditis model group. Administration of FSC231 protected the injury of myocardium and reduced the content of LDH. The levels of malondialdehyde in myocardium significantly decreased in FSC231-treated group. The protein expression of PKCα and PICK1 increased in ADR-induced toxic myocarditis model group. Treatment with FSC231 did not reduced the expression of PKCα. Administration of FSC231 failed to reduced the total membrane and cytolic expression of PICK1 but inhibited the increasing membrane expression of PICK1. Conclusions These findings indicate that the protective effect of PICK1 on ADR-induced toxic myocarditis is involved in the alleviation of myocardium injury by reducing oxidative stress partially via inhibition of PICK1 protein. This work was supported by the National Nature Science Foundation of China (NSFC) Grant 81000576 to Fei Cai, and NSFC Grant 31000249 to JH Wang, and Foundation of Department of Education of Hubei Province Q20112801, 20112804 to Fei Cai, and Cai-Rong Li