Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation

• Published in: International journal of molecular sciences 2020-04, Vol.21 (7), p.2608
• Main Authors: Hsieh, Dennis Jine-Yuan, Ng, Shang-Chuan, Zeng, Ren-You, Padma, Viswanadha Vijaya, Huang, Chih-Yang, Kuo, Wei-Wen
• Format: Article
• Language: English
• Subjects: Activation; Advanced glycosylation end products; AGE; Allyl Compounds - pharmacology; Animals; Antioxidants; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; cardiomyocyte; Cardiomyocytes; Cardiomyopathy; Cell cycle; Cell Survival - drug effects; Cell viability; Cytochrome; Damage assessment; DATS; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental; Diallyl trisulfide; Enzyme Activation - drug effects; Garlic; Glycation End Products, Advanced - pharmacology; Glycosylation; Heart; Heart attacks; Humans; Ischemia; Kinases; Mitochondria; Models, Biological; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Neonates; Oxidative stress; Phosphorylation - drug effects; PKCδ; Plasmids; Protein kinase C; Protein Kinase C-delta - metabolism; Proteins; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Streptozocin; Sulfides - pharmacology; Ventricle
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21072608

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.