Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy

Autor: Jia-Hong Xue, Chuan Qiu, Jin-Ru Wei, Haitao Zhu, Zhongwei Liu, Kun-Lun Chen, Xin Dong
Rok vydání: 2013
Předmět:
medicine.medical_specialty
Diabetic Cardiomyopathies
Endocrinology
Diabetes and Metabolism
Apoptosis
Diabetic cardiomyopathy
Protein Serine-Threonine Kinases
medicine.disease_cause
Diabetes Mellitus
Experimental
Rats
Sprague-Dawley
eIF-2 Kinase
Internal medicine
Medicine
Animals
ASK1
Myocytes
Cardiac
Protein kinase A
Cells
Cultured
Original Investigation
chemistry.chemical_classification
Reactive oxygen species
EIF-2 kinase
biology
business.industry
Endoplasmic reticulum
Membrane Proteins
Free Radical Scavengers
Endoplasmic Reticulum Stress
Cell biology
Acetylcysteine
Activating Transcription Factor 6
Rats
Disease Models
Animal
Endocrinology
Glucose
chemistry
Oxidative stress
Gene Knockdown Techniques
Unfolded protein response
biology.protein
Signal transduction
Cardiology and Cardiovascular Medicine
business
Reactive Oxygen Species
Signal Transduction
Zdroj: Cardiovascular Diabetology
ISSN: 1475-2840
Popis: 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.
Databáze: OpenAIRE
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