Signaling Pathways Related to Oxidative Stress in Diabetic Cardiomyopathy

Abstract

Diabetes is a chronic metabolic disease that is increasing in prevalence and causes many complications. Diabetic cardiomyopathy (DCM) is a complication of diabetes that is associated with high mortality, but it is not well defined. Nevertheless, it is generally accepted that DCM refers to a clinical disease that occurs in patients with diabetes and involves ventricular dysfunction, in the absence of other cardiovascular diseases, such as coronary atherosclerotic heart disease, hypertension, or valvular heart disease. However, it is currently uncertain whether the pathogenesis of DCM is directly attributable to metabolic dysfunction or secondary to diabetic microangiopathy. Oxidative stress (OS) is considered to be a key component of its pathogenesis. The production of reactive oxygen species (ROS) in cardiomyocytes is a vicious circle, resulting in further production of ROS, mitochondrial DNA damage, lipid peroxidation, and the post-translational modification of proteins, as well as inflammation, cardiac hypertrophy and fibrosis, ultimately leading to cell death and cardiac dysfunction. ROS have been shown to affect various signaling pathways involved in the development of DCM. For instance, OS causes metabolic disorders by affecting the regulation of PPARα, AMPK/mTOR, and SIRT3/FOXO3a. Furthermore, OS participates in inflammation mediated by the NF-κB pathway, NLRP3 inflammasome, and the TLR4 pathway. OS also promotes TGF-β-, Rho-ROCK-, and Notch-mediated cardiac remodeling, and is involved in the regulation of calcium homeostasis, which impairs ATP production and causes ROS overproduction. In this review, we summarize the signaling pathways that link OS to DCM, with the intention of identifying appropriate targets and new antioxidant therapies for DCM.

Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study

“… 13 , 32 Experiments with cardiomyocytes in culture have shown that supplementation with 14,15-EET reduces high glucose-induced hypertrophy 33 ; and reduction of EETs by CYP2J2 inhibition reduces the survival of adult ventricular myocytes submitted to reactive oxygen species (ROS), 34 a component of diabetes pathogenesis. 35 In experimental models of diabetes in rodents, mice with cardiac hypertrophy show a decrease in 14,15-EET 33 ; overexpression of CYP2J2 in mice attenuates diabetes-induced myocardial hypertrophy 36 ; and treatment of diabetic rats with a sEH inhibitor attenuates the reduction in cardiac outputs, left ventricular hypertrophy and fibrosis induced by hyperglycemia. 37 These experimental models provide strong evidence that EETs protect the diabetic heart, although how this might translate to a reduced risk of MI in humans is not known.…”

Diabetic cardiomyopathy: The role of microRNAs and long non-coding RNAs

“…Both types of DM are characterized by decreased insulin signaling and changes in other signaling cascades, such as reduced AMPK and increased PKC and MAPK signaling, with resultant deleterious and maladaptive effects ( 3 ). DCMP’s clinical presentation may be preceded by myocardial structure changes and disturbed Ca 2+ signaling and metabolism ( 2 , 4 , 7 , 22 ). The myocardial structure changes, i.e., myocardial fibrosis, are favoured by increased collagen deposition and variations in extracellular matrix (ECM) protein structure ( 40 ).…”

“…Also, microvascular disease and cardiac capillary rarefaction contribute to severe cardiovascular morbidity and mortality in DM patients (3,4). Diabetes-related cardiomyopathy (DCMP) represents DM-induced morphofunctional cardiac abnormality after the presence of valvular, atherosclerotic, congenital, or hypertensive heart disease is excluded (5)(6)(7). Clinically, DCMP can be presented as two distinctive phenotypes, restrictive (heart failure with preserved ejection fraction, HFpEF) and dilated (heart failure with reduced ejection fraction, HFrEF) (8,9).…”

O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice

“…These studies clearly show that NFAT is one of the most important molecules for inducing cardiac hypertrophy and GSK-3β is a critical negative regulator of cardiac hypertrophy signaling pathways. O -GlcNAcylation plays several roles in the impairment of cardiac function via modification of several of the proteins involved in progression to heart failure ( 3 , 28 , 29 ). In the present study, we used Ogt transgenic ( Ogt -Tg) mice and induced heart failure by transverse aortic constriction (TAC) surgery to investigate the role of O -GlcNAcylation in cardiac hypertrophy.…”