Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Hsieh, Dennis Jine-Yuan, Ng, Shang-Chuan, Zeng, Ren-You, Padma, Viswanadha Vijaya, Huang, Chih-Yang, Kuo, Wei-Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178155/
https://www.ncbi.nlm.nih.gov/pubmed/32283691
http://dx.doi.org/10.3390/ijms21072608
_version_ 1783525390075035648
author Hsieh, Dennis Jine-Yuan
Ng, Shang-Chuan
Zeng, Ren-You
Padma, Viswanadha Vijaya
Huang, Chih-Yang
Kuo, Wei-Wen
author_facet Hsieh, Dennis Jine-Yuan
Ng, Shang-Chuan
Zeng, Ren-You
Padma, Viswanadha Vijaya
Huang, Chih-Yang
Kuo, Wei-Wen
author_sort Hsieh, Dennis Jine-Yuan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7178155
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-71781552020-04-28 Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation Hsieh, Dennis Jine-Yuan Ng, Shang-Chuan Zeng, Ren-You Padma, Viswanadha Vijaya Huang, Chih-Yang Kuo, Wei-Wen Int J Mol Sci Article 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. MDPI 2020-04-09 /pmc/articles/PMC7178155/ /pubmed/32283691 http://dx.doi.org/10.3390/ijms21072608 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hsieh, Dennis Jine-Yuan
Ng, Shang-Chuan
Zeng, Ren-You
Padma, Viswanadha Vijaya
Huang, Chih-Yang
Kuo, Wei-Wen
Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation
title Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation
title_full Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation
title_fullStr Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation
title_full_unstemmed Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation
title_short Diallyl Trisulfide (DATS) Suppresses AGE-Induced Cardiomyocyte Apoptosis by Targeting ROS-Mediated PKCδ Activation
title_sort diallyl trisulfide (dats) suppresses age-induced cardiomyocyte apoptosis by targeting ros-mediated pkcδ activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178155/
https://www.ncbi.nlm.nih.gov/pubmed/32283691
http://dx.doi.org/10.3390/ijms21072608
work_keys_str_mv AT hsiehdennisjineyuan diallyltrisulfidedatssuppressesageinducedcardiomyocyteapoptosisbytargetingrosmediatedpkcdactivation
AT ngshangchuan diallyltrisulfidedatssuppressesageinducedcardiomyocyteapoptosisbytargetingrosmediatedpkcdactivation
AT zengrenyou diallyltrisulfidedatssuppressesageinducedcardiomyocyteapoptosisbytargetingrosmediatedpkcdactivation
AT padmaviswanadhavijaya diallyltrisulfidedatssuppressesageinducedcardiomyocyteapoptosisbytargetingrosmediatedpkcdactivation
AT huangchihyang diallyltrisulfidedatssuppressesageinducedcardiomyocyteapoptosisbytargetingrosmediatedpkcdactivation
AT kuoweiwen diallyltrisulfidedatssuppressesageinducedcardiomyocyteapoptosisbytargetingrosmediatedpkcdactivation