Role of Oxidative Stress in Diabetic Cardiomyopathy

Abstract

Type 2 diabetes is a redox disease. Oxidative stress and chronic inflammation induce a switch of metabolic homeostatic set points, leading to glucose intolerance. Several diabetes-specific mechanisms contribute to prominent oxidative distress in the heart, resulting in the development of diabetic cardiomyopathy. Mitochondrial overproduction of reactive oxygen species in diabetic subjects is not only caused by intracellular hyperglycemia in the microvasculature but is also the result of increased fatty oxidation and lipotoxicity in cardiomyocytes. Mitochondrial overproduction of superoxide anion radicals induces, via inhibition of glyceraldehyde 3-phosphate dehydrogenase, an increased polyol pathway flux, increased formation of advanced glycation end-products (AGE) and activation of the receptor for AGE (RAGE), activation of protein kinase C isoforms, and an increased hexosamine pathway flux. These pathways not only directly contribute to diabetic cardiomyopathy but are themselves a source of additional reactive oxygen species. Reactive oxygen species and oxidative distress lead to cell dysfunction and cellular injury not only via protein oxidation, lipid peroxidation, DNA damage, and oxidative changes in microRNAs but also via activation of stress-sensitive pathways and redox regulation. Investigations in animal models of diabetic cardiomyopathy have consistently demonstrated that increased expression of the primary antioxidant enzymes attenuates myocardial pathology and improves cardiac function.

Inhibition of GCN2 Alleviates Cardiomyopathy in Type 2 Diabetic Mice via Attenuating Lipotoxicity and Oxidative Stress

“…In addition, GCN2iB also decreased the mRNA levels of lipid metabolism-related genes, including CD36 , Fasn , Plin4 , Plin2 , Ppar γ , SCD1 and Srebp1c ( Figure 4 B). Lipid accumulation is associated with oxidative stress, which plays an important role in the development of DCM [ 28 ]. GCN2iB treatment resulted in significant decreases in myocardial 3′-NT and 4-HNE levels ( Figure 4 C,D).…”

The Role of PKC-MAPK Signalling Pathways in the Development of Hyperglycemia-Induced Cardiovascular Complications

“…All the results emphasise the unique characteristics of diabetes-associated atherosclerosis. In fact, it is also well established that increased myocardial PKC activity could be observed after chronic or persistent diabetes [ 13 , 14 ].…”

Detrimental Effects of Lipid Peroxidation in Type 2 Diabetes: Exploring the Neutralizing Influence of Antioxidants

“…Furthermore, biomarkers of cardiometabolic diseases, such as low-density lipoprotein and total cholesterol, in relation with oxidative stress, are much higher in these patients when compared to non-diabetic controls [ 71 , 81 ]. Figure 2 gives a general perspective to highlight some of the pathological consequences of oxidative stress in conditions of hyperglycemia; of which lipid peroxidation is a major component that correlated positively with protein as well as nucleic acid oxidation which is indicated by increased advanced glycation end products (AGEs) and 8-hydroxydeoxyguanosine (8-OHDG), respectively [ 83 , 84 ]. Therefore, decreasing or limiting the formation of lipid peroxidation products could be beneficial in restricting the deleterious effects of oxidative stress in T2D.…”