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New Insights on Oxidative Stress and Diabetic Complications May Lead to a “Causal” Antioxidant Therapy

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New Insights on Oxidative Stress and Diabetic Complications May Lead to a “Causal” Antioxidant Therapy Reviews/Commentaries/Position Statements REVIEW ARTICLE New Insights on Oxidative Stress and Diabetic Complications May Lead to a “Causal” Antioxidant Therapy ANTONIO CERIELLO, MD Recent basic and clinical studies have uncovered new insights into the role of oxidative stress in diabetic complications, ABSTRACT—Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of suggesting a different and innovative ap- diabetic complications. However, intervention studies with classic antioxidants, such as vitamin proach to a possible “causal” antioxidant E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hypergly- therapy. The aim of this review is to give cemia-induced process of overproduction of superoxide by the mitochondrial electron-transport an update on this topic. chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased HYPERGLYCEMIA, hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide OXIDATIVE STRESS, AND generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon ENDOTHELIAL favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA DYSFUNCTION — Vascular func- damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) tion in diabetes has been studied exten- polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concen- ϩ sively in both animal models and tration of its substrate NAD , slowing the rate of glycolysis, electron transport, and ATP forma- humans. Impaired endothelium-depen- tion, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dent vasodilation has been a consistent dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. These new findings may explain why classic antioxidants, such as vita- finding in animal models of diabetes in- min E, which work by scavenging already-formed toxic oxidation products, have failed to show duced by alloxan or streptozotocin beneficial effects on diabetic complications and may suggest new and attractive “causal” antiox- (9,10). Similarly, studies in humans with idant therapy. New low–molecular mass compounds that act as SOD or catalase mimetics or type 1 or type 2 diabetes have found en- L-propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, im- dothelial dysfunction when compared proving mitochondrial function and reducing DNA damage, may be good candidates for such a with vascular function in nondiabetic strategy, and preliminary studies support this hypothesis. This “causal” therapy would also be subjects (11,12). associated with other promising tools such as LY 333531, PJ34, and FP15, which block the ␤ In vitro, the direct role of hyperglyce- protein kinase isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While mia has been suggested by evidence that waiting for these focused tools, we may have other options: thiazolinediones, statins, ACE arteries isolated from normal animals, inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property. which are subsequently exposed to exog- enous hyperglycemia, also exhibit atten- Diabetes Care 26:1589–1596, 2003 uated endothelium-dependent relaxation (13). Consistently, in vivo studies have also demonstrated that hyperglycemia di- rectly induces, both in diabetic and nor- he relationship between diabetes It has been suggested that, in diabe- mal subjects, an endothelial dysfunction and premature vascular disease is tes, oxidative stress plays a key role in the (14,15). well established (1). Recent pro- pathogenesis of vascular complications, T The role of free radicals generation in spective studies indicate that long-term both microvascular and macrovascular producing the hyperglycemia-dependent glycemic control is an important predictor (6), and an early marker of such damage is endothelial dysfunction is suggested by not only of microvascular disease (2,3), but the development of an endothelial dys- studies showing that both in vitro (16,17) also of macrovascular complications (4). function (6,7). However, the role of oxi- and in vivo (18–21), the acute effects of Vascular endothelial cells are an im- dative stress in diabetes is questioned by hyperglycemia is counterbalanced by portant target of hyperglycemic damage, the results of intervention studies with an- antioxidants. but the mechanisms underlying this dam- tioxidants, which are elusive or unsuc- age are not fully understood (5). cessful (8). ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● Increased superoxide production in endothelial cells during From the Department of Pathology and Medicine, Experimental and Clinical, Chair of Internal Medicine, University of Udine, Udine, Italy. hyperglycemia: the unifying Address correspondence and reprint requests to Prof. Antonio Ceriello, Chair of Internal Medicine, University hypothesis for the development of of Udine, P.le S. Maria della Misericordia, 33100 Udine, Italy. E-mail: [email protected]. diabetic complications Received for publication 2 May 2002 and accepted in revised form 12 February 2003. Brownlee (22) recently pointed out the Abbreviations: AT1, angiotensin 1; NF, nuclear factor; NO, nitric oxide; NOS, nitric oxide synthase. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion key role of superoxide production in en- factors for many substances. dothelial cells at the mitochondrial level © 2003 by the American Diabetes Association. during hyperglycemia in the pathogenesis DIABETES CARE, VOLUME 26, NUMBER 5, MAY 2003 1589 Causal antioxidant therapy for diabetic complications genes related to vascular stress response (26). Figure 1 summarizes this finding. SUPEROXIDE, NITRIC OXIDE, PEROXYNITRITE, AND NITROTYROSINE FORMATION — Even increased su- peroxide generation in hyperglycemia is a key event in activating the other pathways involved in the pathogenesis of diabetic complications; it represents only a first step in the production of the endothelial dysfunction in diabetes. Nitric oxide (NO) production plays a central role in modulating endothelial function (27). NO is generated from the metabolism of L-arginine by the enzyme nitric oxide synthase (NOS), of which there are three isoforms: the constitutive Figure 1—In endothelial cells, glucose can pass freely through the cell membrane in an insulin- types, brain (bNOS) and endothelial independent manner via GLUT1. Intracellular hyperglycemia induces overproduction of super- (eNOS), and the inducible type, iNOS oxide at the mitochondrial level. Overproduction of superoxide is the first and key event in the (28). iNOS is induced de novo by various activation of all other pathways involved in the pathogenesis of diabetic complications, such as stimuli, including hyperglycemia (29), polyol pathway flux, increased advanced glycosylation end product (AGE) formation, activation ␬ while the mitochondrial-generated super- of protein kinase C (PKC) and NF- B, and increased hexosamine pathway flux. oxide can inhibit eNOS, although enough NO is still produced (30). of diabetic complications. This new in- oxidoreductase), one of the four inner The superoxide anion may quench sight is consistent with the four pathways membrane–associated complexes central NO, thereby reducing the efficacy of a suggested to be involved in the develop- to oxidative phosphorylation. The data in potent endothelium-derived vasodila- ment of diabetic complications (increased the papers (23) indicate that, at least in tor system that participates in the general polyol pathway flux, increased advanced the cell culture, endothelium in an envi- homeostasis of the vasculature (31), and glycosylation end product formation, ac- ronment mimicking physiological hyper- evidence suggests that during hyperglyce- tivation of protein kinase C, and increased glycemia cannot control its appetite for mia, reduced NO availability exists (14). hexosamine pathway flux) and with a uni- glucose. Accelerated flux of glucose The activation of protein kinase C, fying hypothesis regarding the effects of through glycolysis and feeding of pyru- due to superoxide overproduction, in- hyperglycemia on cellular dysfunction vate (thus formed) to the tricarboxylic duces a de novo synthesis of the enzyme (23,24). The authors used endothelial acid cycle overloads mitochondria, caus- NAD(P)H oxidase, which significantly cells subjected to physiologically relevant ing excessive generation of free radicals. contributes to produce more superoxide glucose concentrations as a model system Although oxygen free radicals have been anions (32). for analyzing the vascular response to hy- shown to have a physiological role in sig- Hyperglycemia also favors, through perglycemia because the non-insulin- nal transduction, their sustained genera- the activation of NF-␬B, an increased ex- dependent glucose transporter GLUT1 tion at the levels shown in endothelial pression of both NAD(P)H and iNOS facilitates diffusion of high levels of glu- cells exposed
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