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

Abstract

BackgroundEndoplasmic 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.MethodsIn 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.Resultswe 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.ConclusionsROS- 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.

Matrine pretreatment improves cardiac function in rats with diabetic cardiomyopathy via suppressing ROS/TLR-4 signaling pathway

“…Regarding the destructive aspects of oxidative stress, excess ROS formation has been linked to the activation of apoptotic cascades in different cell types [37,38] . Moreover, accumulating evidence suggests that hyperglycemia causes apoptosis in cardiomyocytes by stimulating ROS production [39][40][41] . Therefore, excessive ROS represent critical and central mediators of the complicated cascades associated with myocardial cell apoptosis in the setting of DCM.…”

Oxidative stress/PERK/apoptotic pathways interaction contribute to tramadol neurotoxicity in rat cerebral and cerebellar cortex and thyme enhances the antioxidant defense system: histological, immunohistochemical and ultrastructural study

“…[10][11][12] A model called ROS dependent ER stress have been concurrently explained to indicate the two stresses that are closely linked events in cellular homeostasis and apoptosis. 11,12 The molecular events coupling ROS and components of ER stress is yet to be fully elucidated. Meanwhile, changes in protein folding pathways produces an ROS imbalance, indirectly disturbing both ER and redox homeostasis and this response can be reversed by antioxidants like thyme vulgaris.…”

Hydrogen sulfide exhibits cardioprotective effects by decreasing endoplasmic reticulum stress in a diabetic cardiomyopathy rat model

“…In addition, in diabetic heart tissue, the ER was found to be swollen and dilated following ultrastructural analysis, suggesting abnormalities in the ER in a hyperglycemic environment (69)(70)(71). Recently, an increasing number of studies have investigated the correlation between ER stress and DC (18,30,31). H 2 S was found to be the third gaseous signaling molecule, which is involved in neuromodulation, neuroprotection, vasodilatation, cardioprotection and regulation of the inflammatory response.…”

“…Cellular metabolic abnormalities and defections of organelles were shown to participate in the pathology of DC (10)(11)(12)(13)(14), which is a chronic and complex process associated with impaired calcium homeostasis, increased lipid uptake, myocardial insulin resistance, glucotoxicity, increased oxidative stress and activation of the renin-angiotensin system (15). Furthermore, the pathological role of endoplasmic reticulum (ER) stress in DC has been noted in a number of studies (16)(17)(18).…”