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Excessive production of reactive oxygen species (ROS) with increased apoptosis in the cardiac tissue are suggested to be responsible for diabetic cardiomyopathy (DCM). Until recently, whether PICK1, the protein interacting with C-kinase 1, can protect the heart against DCM remained unclear. The aim of this study was to determine whether administration of FSC231, a specific PICK1 inhibitor, could ameliorate myocardial injury in DCM rats.
Male Sprague-Dawley rats were randomly divided into three groups: control group (CON), diabetic cardiomyopathy group (DCM), and FSC231-treated diabetic group (DCM+FSC231). Diabetes was induced by intraperitoneal injection (ip) with streptozotocin (50 mg/kg). Eight weeks after the induction of diabetes, DCM+FSC231 group were treated with FSC231 (39.2μg/kg/day, ip) for 4 weeks. At the end of the treatment, cardiac catheterization was performed to evaluate cardiac function. The levels of creatine phosphokinase isoenzyme (CK-MB) and myocardial collagen volume fraction (CVF) were measured. Differential levels of ROS, PKC/PICK1 signaling pathway, and apoptosis were evaluated in cardiac tissues.
Cardiac function was found to be significantly decreased in DCM rats and treatment with FSC231 restored the ratio to baseline. The DCM rats showed increased CK-MB, CVF and ROS production, increased expressions of PKC and PICK1, and decreased phospho-eNOS expression, cGMP concentration and Bcl-2/Bax ratio. FSC231 treatment prevented the increased CK-MB, CVF, ROS production and expression of PICK1. It also significantly reversed the phospho-eNOS expression, increased the cGMP concentration, restored the Bcl-2/Bax ratio. But the expression of PKC was not affected by FSC231 treatment.
Collectively, these findings indicate that PICK1 inhibition could prevent the development of DCM by suppressing reactive oxygen species generation and apoptosis partly via PICK1/eNOS/cGMP pathway.
This work was supported by the National Nature Science Foundation of China (NSFC) Grant 81470049 to Fei Cai, and Foundation of Department of Education of Hubei Province Q20142802 to Fei Cai