Matrine alleviates AGEs- induced cardiac dysfunctions by attenuating calcium overload via reducing ryanodine receptor 2 activity.

Featured by heart dysfunction, the diabetic cardiomyopathy is causing mortality and morbidity in type 2 diabetes mellitus patients. Matrine was considered as a cardioprotective agent. This study was aimed to investigate the therapeutic effects and molecular mechanisms of matrine on advanced glycation end products (AGEs)- induced cardiac dysfunctions. Rats and isolated primary myocytes were exposed to AGEs. Left ventricular hemodynamic parameters were used to assess the cardiac function. Cell apoptosis was detected with TUNEL assay. Calcium indicator was used to determine the intracellular calcium concentration ([Ca2+]i). The molecular coupling between FK506-binding protein 12.6 (FKBP12.6) and ryanodine receptor 2 (RyR2) was evaluated by immunoprecipitation. Apoptotic protein expressions were measured by western blotting. The activity of RyR2 was measured by [3H]-ryanodine binding assay. AGEs exposure impaired systolic and diastolic functions and induced apoptosis in myocardium. AGEs exposure also elevated [Ca2+]i, decreased mitochondrial membrane potential (MMP) and induced cell apoptosis in myocardium and cultured myocytes. AGEs impaired association between FKBP12.6 and RyR2 and further increased RyR2 activity in vivo and in vitro. The expression levels of cytochrome c and active caspase3 were elevated by AGEs exposure. Matrine treatment improved cardiac function in AGEs- exposed hearts. Matrine inhibited the disassociation of FKBP12.6 and RyR2, decreased the activity of RyR2, [Ca2+]i, apoptosis, expression levels of cytochrome c and active caspase3 in vivo and in vitro. Matrine attenuated AGEs- induced cardiac dysfunctions by regulating RyR2- mediated calcium overload- triggered myocardial apoptosis.