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

Int J Mol Sci. 2020 Apr 9;21(7):2608. doi: 10.3390/ijms21072608.

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.

Keywords: AGE; DATS; PKCδ; apoptosis; cardiomyocyte.

MeSH terms

  • Allyl Compounds / pharmacology*
  • Animals
  • Antioxidants / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Survival / drug effects
  • Diabetes Mellitus, Experimental
  • Enzyme Activation / drug effects
  • Glycation End Products, Advanced / pharmacology*
  • Humans
  • Models, Biological
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinase C-delta / metabolism*
  • Rats
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction / drug effects
  • Sulfides / pharmacology*

Substances

  • Allyl Compounds
  • Antioxidants
  • Apoptosis Regulatory Proteins
  • Glycation End Products, Advanced
  • Reactive Oxygen Species
  • Sulfides
  • diallyl trisulfide
  • Protein Kinase C-delta