Role of Antioxidants in Redox Regulation of Diabetic Cardiovascular Complications

Belma      Turan

doi:10.2174/138920110793262123

Abstract

Cardiovascular dysfunction is leading cause for the mortality of diabetic individuals, in part due to a specific cardiomyopathy, and due to altered endothelial dependent/independent vascular reactivity. Cardiovascular complications result from multiple parameters including glucotoxicity, lipotoxicity, fibrosis and mitochondrial uncoupling. Oxidative stress arises from an imbalance between the production of reactive oxygen and nitrogen species (ROS and RNS) and the capability of biological system to readily detoxify reactive intermediates. Several studies have reported beneficial effects of a therapy with antioxidant agents, including trace elements and other antioxidants, against the cardiovascular system dysfunction due to the diabetes. Antioxidants act through different mechanisms to prevent oxidant-induced cell damages acting either directly or indirectly. They can reduce the generation of ROS, scavenge ROS, or interfere with ROS-induced alterations. Modulating mitochondrial activity is an important possibility to control ROS production. Hence, the use of PPAR agonist to reduce fatty acid oxidation and of trace elements such as selenium as antioxidant and other antioxidants such as vitamins E and C, contribute to the prevention of diabetes-induced cardiovascular dysfunction. The paradigm that, inhibiting the overproduction of superoxides and peroxides would prevent cardiac dysfunction in diabetes has been difficult to verify using conventional antioxidants like vitamins E and C, that led to use of catalytic antioxidants such as SOD/CAT mimetics. Hence, well-tuned, balanced and responsive antioxidant defence systems are vital for proper prevention against diabetic damage. Myocardial cell death is observed in the hearts of diabetic patients and animal models; however, its importance in the development of diabetic cardiomyopathy is not completely understood. This review aims to summarize our present knowledge on various strategies to control oxidative stress and antagonize cardiovascular dysfunction during diabetes. In here, I consider aspects of redox signaling in the cardiovascular system, focusing on the molecular basis of redox sensing by proteins and the array of post-translational oxidative modifications that can occur. In addition, I discuss studies identify redox-sensitive cardiac proteins, as well as those assessing redox signalling in cardiovascular disease.

Keywords: Oxidant stress, antioxidants, selenium, vitamin E, vitamin C, heart, vessel, diabetes, redox cycle, glutathion, Cardiovascular dysfunction, cardiomyopathy, glucotoxicity, lipotoxicity, fibrosis, mitochondrial uncoupling, Myocardial cell death, thioredoxin, lipid peroxidation, nucleic acids, redox signalling, hyperglycemia, reactive oxygen species (ROS), hypertension, homeostatic pathways, glutathione, hydrogen peroxide, hypochlorite, ozone, xanthine, hypoxanthine, tyrosine, cysteine, apoptosis, cytolysis, Xanthine oxidase, Cytochrome P450 (CYP), arachidonic acid, Glutathione peroxidase (GSHPx), glutathione reductase (GR), thioredoxin (Trx), superoxide reductase (SOR), catalase (CAT), cardiomyocytes, Ca2+ channels, sarcoplasmic reticulum (SERCA), matrix metalloproteins (MMPs), homeostasis, ryanodine receptors (RyR2), advanced glycation end products (AGEs), protein kinase A (PKA), reactive nitrogen species (RNS), protein kinase C (PKC), nuclear factor kappa B (NF-B), N-acetyl-L-cysteine (NAC), glucose-6-phosphate deshydrogenase (G6PD), tetrahydrobiopterin (BH4), nitric oxide (NO), poly(ADP-ribose) polymerase (PARP), insulinsensitizing agents, metallothioneins (MTs), Selenium Compounds, Heart Outcomes Prevention Evaluation, [HOPE], revascularizations, nephropathy, creatine phosphokinase (CPK-MB), lactic dehydrogenase (LDH), serum glutamic oxaloacetic transaminase (SGOT), myocardial infarction, lipophilic antioxi-dant, Angiotensin converting enzyme (ACE), bosentan, polyunsaturated fatty acids, biscyclohexylpyridine, Beta-adrenergic receptors, Creatine phosphokinase, Glutaredoxin system, Isopreterenol, Nitric oxide radical, Nitric oxide synthase, Superoxide anion, Hydroxyl radical, Peroxynitrite, Peroxisome proliferator-activated receptors, 6-phosphogluconate dehydrogenase, Sulfenic acid derivatives, Protein sulfhydryl (thiol)