Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes

Abstract

Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress. mTOR signaling presents both cardioprotective and cardiotoxic effects on the diabetic heart, which interplays with oxidative stress directly or indirectly. Antihyperglycemic agent metformin and newly found free radicals scavengers, Sirt1 and CTRP9, may serve as promising pharmacological therapeutic targets. In this review, we will focus on the role of oxidative stress and mTOR signaling in the pathophysiology of MI/R injury in diabetes and discuss potential mechanisms and their interactions in an effort to provide some evidence for cardiometabolic targeted therapies for ischemic heart disease (IHD).

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

“…Autophagy is described as a physiological process involved in antioxidant defense [62] and autophagy deficiency clearly results in neuronal loss and neurodegeneration in mice [63]. On the other hand, induction of autophagy is shown to alleviate oxidative stress in myocardial ischemia/reperfusion Injury [64].…”

“…ROS production i.e. oxidative stress is known to inhibit mTORC1 [64], [70], the major regulatory complex for autophagy induction. Interestingly, in OxSR cells the increase in autophagy under chronic oxidative stress is not mediated via mTOR inhibition, whereas the classical BECN1/PI3K3C3 complex obviously is involved and highly upregulated in their expression in OxSR cells ( Figure 2).…”

The efficacy of black cumin seed (Nigella sativa) oil and hypoglycemic drug combination to reduce HbA1c level in patients with metabolic syndrome risk

“…If this condition is prolonged, irreversible advanced glycosylation end products (AGE) will be formed on the walls of blood vessels that may be potentially pathogenic and lead to diabetic complications [12,13]. Increased AGE results in cellular and tissue oxidative stress, causing damage to tissues and blood vessel cells, especially the endothelium tissue and generating an inflammatory reaction [10,14].…”

Biological Effects and Properties of Eukaryotic Sirtuins

“…Його активація, в свою чергу, призводить до глюконеогенезу, що пригнічує гліколіз. SIRT1 може впливати на PGC-1α також за допомогою AMPK, FOXO1, STAT3 [24,27,[43][44][45][46][47]. Окрім цього, встанов-лена роль сиртуїнів у ліпідному обміні та при утворенні жирових клітин [48,49].…”