Reduced silent information regulator 1 signaling exacerbates myocardial ischemia–reperfusion injury in type 2 diabetic rats and the protective effect of melatonin

Abstract

Diabetes mellitus (DM) increases myocardial oxidative stress and endoplasmic reticulum (ER) stress. Melatonin confers cardioprotective effect by suppressing oxidative damage. However, the effect and mechanism of melatonin on myocardial ischemia-reperfusion (MI/R) injury in type 2 diabetic state are still unknown. In this study, we developed high-fat diet-fed streptozotocin (HFD-STZ) rat, a well-known type 2 diabetic model, to evaluate the effect of melatonin on MI/R injury with a focus on silent information regulator 1 (SIRT1) signaling, oxidative stress, and PERK/eIF2α/ATF4-mediated ER stress. HFD-STZ treated rats were exposed to melatonin treatment in the presence or the absence of sirtinol (a SIRT1 inhibitor) and subjected to MI/R surgery. Compared with nondiabetic animals, type 2 diabetic rats exhibited significantly decreased myocardial SIRT1 signaling, increased apoptosis, enhanced oxidative stress, and ER stress. Additionally, further reduced SIRT1 signaling, aggravated oxidative damage, and ER stress were found in diabetic animals subjected to MI/R surgery. Melatonin markedly reduced MI/R injury by improving cardiac functional recovery and decreasing myocardial apoptosis in type 2 diabetic animals. Melatonin treatment up-regulated SIRT1 expression, reduced oxidative damage, and suppressed PERK/eIF2α/ATF4 signaling. However, these effects were all attenuated by SIRT1 inhibition. Melatonin also protected high glucose/high fat cultured H9C2 cardiomyocytes against simulated ischemia-reperfusion injury-induced ER stress by activating SIRT1 signaling while SIRT1 siRNA blunted this action. Taken together, our study demonstrates that reduced cardiac SIRT1 signaling in type 2 diabetic state aggravates MI/R injury. Melatonin ameliorates reperfusion-induced oxidative stress and ER stress via activation of SIRT1 signaling, thus reducing MI/R damage and improving cardiac function.

Ginkgolide B Exerts Cardioprotective Properties against Doxorubicin-Induced Cardiotoxicity by Regulating Reactive Oxygen Species, Akt and Calcium Signaling Pathways In Vitro and In Vivo

“…In the investigation of molecular mechanisms, cardiomyocytes were pretreated with 50 μM GB or small molecular inhibitors targeting given metabolic pathways (LY294002 (10 μM) or KN62 (10 μM)) for 30 min before being challenged with 5 μM DOX. After 48 h incubation, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT: 0.5 mg/ml; Sigma, MO, USA)[40–42] was added and further incubated for 4 h, followed by addition of formazan dye dissolved with DMSO in a microplate reader (Biotek Instruments, Winooski, VT) and reading at 570 nm. Cell viability expressed as relative viability compared with control in each experiment.…”

Snapshots: Endoplasmic Reticulum Stress in Lipid Metabolism and Cardiovascular Disease

“…Melatonin markedly reduces MIR injury by downregulating ERS, decreasing myocardial apoptosis, and improving cardiac functional recovery. This suggests that melatonin ameliorates reperfusion-induced myocardial injury via inactivation of ERS (Yu et al, 2015) (Figure 1, Table 1). …”

“…Type 2 diabetic rats exhibit a significantly elevated ERS response. When subjected to MIR surgery, ERS and myocardial injury are enhanced (Yu et al, 2015). Melatonin markedly reduces MIR injury by downregulating ERS, decreasing myocardial apoptosis, and improving cardiac functional recovery.…”

“…Disruption of n o r m a l E R h o m e o s t a s i s m a y i n c r e a s e cardiovascular risk (Chaube et al, 2012;Akoumi et al, 2017), induce hepatic lipid accumulation , cause metabolic disorders (Qin et al, 2015), and induce insulin resistance (Diaz et al, 2015). We previously identified roles for ERS in myocardial ischemia (MI) (Yu et al, 2015;Yu et al, 2016), endothelial cells , and cell apoptosis . In this review, we summarize the roles of ERS in lipid metabolism and CVD with respect to recent advances in research.…”

Erythropoietin and mTOR: A “One-Two Punch” for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

“…For example, DM can negatively impact the immune system, musculoskeletal function, hepatic metabolism, and renal clearance (50, 53, 55, 59, 61–64). In the cardiovascular system, DM can lead to impaired angiogenesis, platelet dysfunction, atherosclerosis, endothelial progenitor cell injury, cardiac impairment, and loss of vascular cells (8, 14, 27, 62, 65–68). In the nervous system, DM results in cortical injury and stroke (62, 67, 69–72), retinal disease (50, 73–75), dementia (76), AD (51, 61, 71, 77), peripheral neuropathy (78, 79), and psychiatric disorders (80, 81).…”