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).

Endoplasmic reticulum (ER) stress, together with the unfolded protein response (UPR), is initially considered an adaptive response aiming at maintenance of ER homeostasis. Nonetheless, ER stress, when in excess, can eventually trigger cell apoptosis and loss of function. UPR is mediated by three major transmembrane proteins, including inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor (ATF) 6. A unique role has been speculated for ER stress in the pathogenesis of diabetes mellitus (DM) and its complications. Recent studies have shown that ER stress is an early event associated with diabetic cardiomyopathy, and may be triggered by hyperglycemia, free fatty acids (FFAs) and inflammation. In this mini-review, we attempted to discuss the activation machinery for ER stress in response to these triggers en route to disrupted ER function and cellular autophagy or apoptosis, ultimately insulin resistance and development of diabetic cardiomyopathy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

Background Exercise benefits to cardiac rehabilitation (CR) following stable myocardial infarction (MI). The suitable exercise duration for aged patients with coronary heart disease (CHD) remains controversial, and the underlying molecular mechanism is still unclear. Methods and Results 18-Month-old mice after stable MI were randomly submitted to different durations of exercise, including 15 and 60 min swimming training (ST) once per day, five times a week for 8 weeks. Compared to sedentary mice, 15 min ST, rather than 60 min ST, significantly augmented left ventricular function, increased survival rate, and suppressed myocardial fibrosis and apoptosis. 15 min ST improved mitochondrial morphology via regulating mitochondrial fission-fusion signaling. 15 min ST regulated mitophagy signaling via inhibiting LC3-II and P62 levels and increasing PINK/Parkin expression. 15 min ST also inhibited ROS production and enhanced antioxidant SOD2 activity. Notably, 15 min ST significantly increased sirtuin (SIRT) 3 level (2.7-fold) in vivo while the inhibition of SIRT3 exacerbated senescent H9c2 cellular LDH release and ROS production under hypoxia. In addition, SIRT3 silencing impairs mitochondrial dynamics and mitophagy in senescent cardiomyocytes against simulated ischemia (SI) injury. Conclusion Collectively, our study demonstrated for the first time that sustained short-duration exercise, rather than long-duration exercise, attenuates cardiac dysfunction after MI in aged mice. It is likely that the positive regulation induced by a short-duration ST regimen on the elevated SIRT3 protein level improved mitochondrial quality control and decreased apoptosis and fibrosis contributed to the observed more resistant phenotype.