Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting

Abstract

Despite being first described 45 years ago, the existence of a distinct diabetic cardiomyopathy remains controversial. Nonetheless, it is widely accepted that the diabetic heart undergoes characteristic structural and functional changes in the absence of ischaemia and hypertension, which are independently linked to heart failure progression and are likely to underlie enhanced susceptibility to stress. A prominent feature is marked collagen accumulation linked with inflammation and extensive extracellular matrix changes, which appears to be the main factor underlying cardiac stiffness and subclinical diastolic dysfunction, estimated to occur in as many as 75% of optimally controlled diabetics. Whether this characteristic remodelling phenotype is primarily driven by microvascular dysfunction or alterations in cardiomyocyte metabolism remains unclear. Although hyperglycaemia regulates multiple pathways in the diabetic heart, increased reactive oxygen species (ROS) generation is thought to represent a central mechanism underlying associated adverse remodelling. Indeed, experimental and clinical diabetes are linked with oxidative stress which plays a key role in cardiomyopathy, while key processes underlying diabetic cardiac remodelling, such as inflammation, angiogenesis, cardiomyocyte hypertrophy and apoptosis, fibrosis and contractile dysfunction, are redox sensitive. This review will explore the relative contributions of the major ROS sources (dysfunctional nitric oxide synthase, mitochondria, xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidases) in the diabetic heart and the potential for therapeutic targeting of ROS signalling using novel pharmacological and non-pharmacological approaches to modify specific aspects of the remodelling phenotype in order to prevent and/or delay heart failure development and progression.

Mitochondrial fusion promoter restores mitochondrial dynamics balance and ameliorates diabetic cardiomyopathy in an optic atrophy 1‐dependent way

“…The dynamic balance of mitochondrial fusion and fission is essential for maintaining cardiomyocyte function, including energy production and cell survival . Emerging data have indicated that both mitochondrial dysfunction and mitochondrial ROS are implicated in the pathogenesis of DCM, whereas the mechanisms underlying mitochondrial damage in DCM are still largely unclear. The incidence of diabetes is unpredictable, therefore it would be more meaningful to mimic clinical scenario if the treatment are given after one period since the onset of diabetes.…”

“…Diabetic cardiomyopathy is characterized by abnormal cardiac structure and function that are independent of coronary artery disease or hypertension . Although excessive production of reactive oxygen species (ROS) and increased apoptotic cell death have been proposed as potential contributed factors in the pathogenesis of DCM, accumulating evidence demonstrates the imbalanced mitochondrial fusion/fission dynamics is an initial cause for these events . Excessive mitochondrial fission has been associated with an overproduction of ROS and increased apoptotic cell death in diabetic hearts.…”

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

“…Lok et al reported that NRG-1 can decrease human brain endothelial cells death after oxidative injury with H 2 O 2 [29]. Oxidative stress caused by mitochondrial superoxide overproduction in endothelial cells is the major mechanism in the development of vascular complications in diabetes [30, 31]. Previous study reported that NRG-1 can alleviate oxidative and endoplasmic reticulum stress in heart [32].…”

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

“…Cardiomyocytes are particularly susceptible to diabetic insults caused by dysfunctional mitochondria 13, 14. Mitochondria that are damaged during diabetic stress can produce reactive oxygen species (ROS) and release death‐inducing factors, thus augmenting cardiomyocyte injury 14, 15, 16…”