Chronic high-glucose exposure results in the production of advanced glycation end-products (AGEs) leading to reactive oxygen species (ROS) generation, which contributes to the development of diabetic cardiomyopathy. PKC delta activation leading to ROS production and mitochondrial dysfunction involved in AGE-induced cardiomyocyte apoptosis was reported in our previous study. Diallyl trisulfide (DATS) is a natural cytoprotective compound under various stress conditions. In this study, the cardioprotective effect of DATS against rat streptozotocin (STZ)-induced diabetic mellitus (DM) and AGE-induced H9c2 cardiomyoblast cell/neonatal rat ventricular myocyte (NRVM) damage was assessed. We observed that DATS treatment led to a dose-dependent increase in cell viability and decreased levels of ROS, inhibition of PKC delta activation, and recuded apoptosis-related proteins. Most importantly, DATS reduced PKC delta mitochondrial translocation induced by AGE. However, apoptosis was not inhibited by DATS in cells transfected with PKC delta-wild type (WT). Inhibition of PKC delta by PKC delta-kinase-deficient (KD) or rottlerin not only inhibited cardiac PKC delta activation but also attenuated cardiac cell apoptosis. Interestingly, overexpression of PKC delta-WT plasmids reversed the inhibitory effects of DATS on PKC delta activation and apoptosis in cardiac cells exposed to AGE, indicating that DATS may inhibit AGE-induced apoptosis by downregulating PKC delta activation. Similar results were observed in AGE-induced NRVM cells and STZ-treated DM rats following DATS administration. Taken together, our results suggested that DATS reduced AGE-induced cardiomyocyte apoptosis by eliminating ROS and downstream PKC delta signaling, suggesting that DATS has potential in diabetic cardiomyopathy (DCM) treatment.
