Melatonin ameliorates myocardial apoptosis by suppressing endoplasmic reticulum stress in rats with long‑term diabetic cardiomyopathy

Abstract

The effects of melatonin (MLT), which exerts cardioprotective effects against myocardial apoptosis, in long‑term diabetic cardiomyopathy are not currently well defined. The present study aimed to investigate how MLT protects the heart through modulating myocardial apoptosis in rats with type 2 diabetes mellitus (DM). In total, 36 rats were randomly divided into three groups, including control (n=12), DM (n=12) and DM + MLT (n=12) groups. The results demonstrated that, in DM rats, a significant increase was observed in the serum fasting blood glucose and lipid levels, in addition to insulin resistance and cardiac dysfunction, which were attenuated in DM rats treated with MLT. Additionally, cellular apoptosis in rats with DM was increased, and the expression of Bcl‑2 was downregulated, while levels of Bcl‑2‑associated X and caspase‑3 were upregulated, and these observations were reversed by MLT, as determined by TUNEL and western blot analysis, respectively. As increased endoplasmic reticulum (ER) stress induced by hyperglycemia is reported to be a factor for apoptosis, the present study also determined the expression of proteins associated with ER stress in cardiac tissues following MLT treatment by western blotting. The results further indicated that MLT decreased the expression of ER stress hallmarks, including CCAAT/enhancer‑binding protein homologous protein, glucose‑regulated protein 78, protein kinase RNA‑like endoplasmic reticulum kinase (PERK) and activating transcription factor 6α in cardiac tissues. In conclusion, the results of the present study indicate that MLT may protect heart by ameliorating cardiac ER stress‑induced apoptosis in diabetic cardiomyopathy.

Melatonin: new insights on its therapeutic properties in diabetic complications

“…Activation of PGC1α-SIRT3 signaling plays a key role in cardioprotective action of melatonin; this signaling pathway leads to the enhancement of mitochondrial SOD activity, oxidative phosphorylation of Complexes I, III and IV, and reduction of mitochondrial lipid peroxidation, ROS generation and myocardial apoptosis [79]. In addition, it has been emphasized that melatonin treatment ameliorates myocardial apoptosis through suppressing ER-stress and spleen tyrosine kinase (Syk)/mitochondrial complex I/sarcoendoplasmic reticulum calcium transport ATPase (SERCA) axis [82,83]. Chronic high-glucose activates Syk leading to the repression of the expression and activity of mitochondrial complex I causing increased generation of ROS and subsequent peroxidation of SERCA; this results in the inhibition of cytoplasmic calcium re-uptake by ER leading to cellular calcium overload and cardiomyocytes death via activation of mitochondria-and ER stress-mediated apoptosis [82,83].…”

Potential Role of Melatonin as an Adjuvant for Atherosclerotic Carotid Arterial Stenosis

“…In a Zucker diabetic fatty rat model, which has a higher initial weight and weight gain, melatonin showed lipid homeostasis regulation in the context of obesity and hyperglycemia [120]. Additionally, melatonin exerts benefits in other hyperglycemia-induced pathological models, including cardiac apoptosis [121], myocardial I/R injury [122], cardiac fibrosis [123], and retinopathy [124]. These findings further confirm the atheroprotective benefits of melatonin in the context of hyperglycemia.…”

Melatonin alleviates hyperglycemic-induced cardiomyocyte apoptosis via regulation of long non-coding RNA H19/miR-29c/MAPK axis in diabetic cardiomyopathy

“…It also published that melatonin could protect the rat heart against diabetesinduced apoptosis through ameliorating metabolic risk factors and modulating apoptotic proteins [43]. Our former research also revealed that melatonin played a positive role against the apoptosis via regulating endoplasmic reticulum stress and MAPK pathways [27,28]. In this study, our data showed that melatonin could not directly decrease blood glucose level in diabetic rats, but it could distinctly ameliorate diabetic cardiac dysfunction independent of regulation of blood glucose level, perhaps partly through reducing myocardial apoptosis via modulation of MAPK signal pathways and apoptosis-related proteins.…”

“…Ding et al elucidated that melatonin participated in preventing Drp1-mediated mitochondrial ssion by regulating SIRT1-PGC1α pathway [26]. In our previous research, melatonin not only prevented diabetic cardiomyocyte apoptosis via inhibiting endoplasmic reticulum stress, but also ameliorated diabetic arterial endothelial permeability by regulating MAPK signaling pathway activation [27,28]. Intriguingly, previous studies have demonstrated the intimate relationship between cardiomyocyte apoptosis and MAPK signal pathways.…”