Author:
Liu Zhong-Wei,Zhu Hai-Tao,Chen Kun-Lun,Dong Xin,Wei Jin,Qiu Chuan,Xue Jia-Hong
Abstract
Abstract
Background
Endoplasmic reticulum (ER) stress is considered one of the mechanisms contributing to reactive oxygen species (ROS)- mediated cell apoptosis. In diabetic cardiomyopathy (DCM), cell apoptosis is generally accepted as the etiological factor and closely related to cardiac ROS generation. ER stress is proposed the link between ROS and cell apoptosis; however, the signaling pathways and their roles in participating ER stress- induced apoptosis in DCM are still unclear.
Methods
In this study, we investigated the signaling transductions in ROS- dependent ER stress- induced cardiomocyte apoptosis in animal model of DCM. Moreover, in order to clarify the roles of IRE1 (inositol - requiring enzyme-1), PERK (protein kinase RNA (PKR)- like ER kinase) and ATF6 (activating transcription factor-6) in conducting apoptotic signal in ROS- dependent ER stress- induced cardiomocyte apoptosis, we further investigated apoptosis in high- glucose incubated cardiomyocytes with IRE1, ATF6 and PERK- knocked down respectively.
Results
we demonstrated that the ER stress sensors, referred as PERK, IRE1 and ATF6, were activated in ROS- mediated ER stress- induced cell apoptosis in rat model of DCM which was characterized by cardiac pump and electrical dysfunctions. The deletion of PERK in myocytes exhibited stronger protective effect against apoptosis induced by high- glucose incubation than deletion of ATF6 or IRE in the same myocytes. By subcellular fractionation, rather than ATF6 and IRE1, in primary cardiomyocytes, PERK was found a component of MAMs (mitochondria-associated endoplasmic reticulum membranes) which was the functional and physical contact site between ER and mitochondria.
Conclusions
ROS- stimulated activation of PERK signaling pathway takes the major responsibility rather than IRE1 or ATF6 signaling pathways in ROS- medicated ER stress- induced myocyte apoptosis in DCM.
Publisher
Springer Science and Business Media LLC
Subject
Cardiology and Cardiovascular Medicine,Endocrinology, Diabetes and Metabolism
Cited by
166 articles.
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