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).

Figure 1

DM-induced higher basal oxidative state plays a master role in the progression of cardiometabolic disorders and negatively affects the MI/R injury. In this state, ROS and RNS accumulate dramatically. They initiate the reaction of ^∙OH in parallel with the ONOO⁻/ONOOH generation, which becomes strong cytotoxic oxidant and causes oxidative damage and nitration. These then lead to endothelium dysfunction, formation of advanced glycation end products, and alteration of the mitochondrial quality control, all contributing to the deleterious MI/R injury in diabetic hearts. Free fatty acid (FFA); protein kinase C-θ (PKC-θ); nuclear factor of kappa light polypeptide gene (NF-κB); superoxide (^∙O₂⁻); hydrogen peroxide (H₂O₂); glutathione peroxidase (GPx); catalase (CAT); hydroxyl (^∙OH); tetrahydrobiopterin (BH4); nitric oxide synthase (NOS); inducible NOS (iNOS); nitric oxide (^∙NO); peroxynitrite (ONOO⁻); peroxynitrous acid (ONOOH); nitrogen dioxide (NO₂); mitochondrial permeability transition pore (mPTP).

Figure 2

The diabetic heart is susceptible to 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 to be more vulnerable to MI/R injury and be resistant to ischemic preconditioning (IPC) or ischemic postconditioning (I-post). Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Reperfusion injury salvage kinase (RISK); phosphoinositide-3 kinase (PI3k); glycogen synthase kinase-3β (GSK-3β); signal transducer and activator of transcription (STAT); autophagy related gene 13 (Atg13); mammalian Atg1 homologues UNC-51-like kinase (ULK); Janus kinase 2 (JAK2); extracellular regulated MAP kinase (ERK).