Abstract
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. PKCδ 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 PKCδ activation, and recuded apoptosis-related proteins. Most importantly, DATS reduced PKCδ mitochondrial translocation induced by AGE. However, apoptosis was not inhibited by DATS in cells transfected with PKCδ-wild type (WT). Inhibition of PKCδ by PKCδ-kinase-deficient (KD) or rottlerin not only inhibited cardiac PKCδ activation but also attenuated cardiac cell apoptosis. Interestingly, overexpression of PKCδ-WT plasmids reversed the inhibitory effects of DATS on PKCδ activation and apoptosis in cardiac cells exposed to AGE, indicating that DATS may inhibit AGE-induced apoptosis by downregulating PKCδ 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 PKCδ signaling, suggesting that DATS has potential in diabetic cardiomyopathy (DCM) treatment.
Highlights
Diabetes mellitus (DM) is the most lethal noncommunicable disease worldwide, with the global prevalence expected to rise to 366 million by 2030 [1,2]
The results showed that Diallyl trisulfide (DATS) did not induce cell damage when the concentration was lower than 10 μM
By exploring the effects of DATS on survival markers, we found that DATS treatment increased p-Akt protein levels, indicating that DATS may maintain cardiomyoblast growth and apoptosis inhibition (Figure 2B)
Summary
Diabetes mellitus (DM) is the most lethal noncommunicable disease worldwide, with the global prevalence expected to rise to 366 million by 2030 [1,2]. PKCδ can be activated by H2O2 and high levels of glucose through increased mitochondrial ROS and enhanced oxidative stress [17,18,19]. Mitochondrial translocation of PKCδ contributes to ischemia–reperfusion injury by inhibiting ATP production and promoting mitochondrial ROS generation, cytochrome c release, caspase activation, and apoptosis induction [20]. Our previous study linked the activation of PKCδ and mitochondrial dysfunction in cardiomyocytes to ROS upregulation in response to AGE exposure. The inhibition of PKCδ signaling pathways may be a good strategy to reduce AGE-induced ROS-mediated mitochondrial dysfunction and apoptosis in cardiomyocytes. We determined whether AGE-induced PKCδ activation and ROS-mediated apoptosis could be attenuated by DATS
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