Oxidative stress, AGE, and atherosclerosis

Abstract

Numerous reports on the molecular mechanism of atherogenesis indicate an increase in oxidative stress, formation of advanced glycoxidation end products (AGEs), chronic inflammation, and activated cellular response particularly in diabetic patients. To elucidate the initiating and early accelerating events this review will focus on the molecular causes of the induction of these stress factors, their interactions, and their contribution to atherogenesis. Metabolic factors such as elevated free fatty acids, high glucose levels or AGEs induce reactive oxygen species (ROS) in vascular cells leading to ongoing AGE formation and to gene induction of proinflammatory cytokines. Vice versa, numerous cytokines found elevated in obesity and diabetes may also induce oxidative stress thus a circulus vitious may be initiated and accelerated. Increased production of ROS, mainly from mitochondria and NAD(P)H oxidase, stimulates signaling cascades including protein kinase C and mitogen-activated protein kinase pathway leading to nuclear translocation of transcription factors such as nuclear factor-kappaB (NF-kappaB), activator protein 1, and specificity protein 1. Subsequently, the expression of numerous genes including cytokines is rapidly induced, which, in turn, may act on vascular cells promoting the deleterious effects. From animal models of accelerated atherosclerosis a causal role of NAD(P)H oxidase and the AGE/RAGE/NF-kappaB axis to atherogenesis is suggested. Because all factors involved form a highly interwoven network of interactions, the blockade of ROS or AGE formation at different sites may interrupt the vicious cycle. Promising candidate agents are, currently on trial. Most important to clinical practice, a number of drugs commonly used in the treatment of diabetes, hypertension, or cardiovascular disease, such as angiotensin-converting enzyme inhibitors, AT(1) receptor blockers, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins), and thiazolidindiones have shown promising 'preventive' intracellular antioxidant activity in addition to their primary pharmacological actions.

A-FABP and Oxidative Stress Underlie the Impairment of Endothelium-Dependent Relaxations to Serotonin and the Intima-Medial Thickening in the Porcine Coronary Artery with Regenerated Endothelium

“…15,17 ROS are key players in the pathogenesis of atherosclerosis. 42 The recruitment of macrophages and the endocytosis of low density lipoprotein generate oxidized low density lipoprotein (oxy-LDL) and ROS, which contribute to the oxidative stress. 43 This not only causes oxidative damage to the eNOS pathway, 44 but by interacting with transcription factors (nuclear factor-κb and activator protein-1) promotes the generation of pro-inflammatory adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1) and cytokines (interleukin-6, tissue necrosis factor-α).…”

Reconvene and Reconnect the Antioxidant Hypothesis in Human Health and Disease

“…Since FR were accused as causal factors in a large number of diseases, these were sometimes referred as ''Free Radical Diseases''. Some of the important diseases and health issues in this category are cancer [61][62][63][64][65][66][67], cardiovascular diseases [68][69][70][71][72][73], atherosclerosis [74][75][76][77][78][79][80][81], neurological disorders [82][83][84][85][86], renal disorders [87][88][89][90], liver disorders [91][92][93], hypertension [50,94,95], rheumatoid arthritis [96,97], adult respiratory distress syndrome, auto-immune deficiency diseases [98,99], inflammation, degenerative disorders associated with aging [100][101][102][103], diabetes mellitus [104][105]…”

Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2

“…Excess generation of ROS in this pathway has been detected but its quantitative contribution to ROS pool is not known. The most important aspect is excess formation of AGEs and RAGE which are undoubtedly participant in the diabetic complications (30,79).…”

“…DMT-2 consequent to hyperglycemia leads to combination of protein and sugar unit in plasma and locally the site of vascular complications. The process is called protein glycation end products formation and products designated as Advanced Glycation End Products (AGEs) and are now establishedly recognized to exert several harmful effects (30,79). The process of protein glycation is initiated by a nucleophilic addition reaction between free amino group of protein and carbonyl group of a reducing sugar, especially glucose in human body.…”

“…Numerous clinical (5,15,42,43,54,62,73,(104)(105)(106)(107) and animal studies demonstrated that these are mainly due to chronic hyperglycemia intercalated by FR and OS (75- 79,108). Usually these complications set after several years of hyperglycemic condition.…”