Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I

MA Creager, TF Lüscher… - Circulation, 2003 - Am Heart Assoc
MA Creager, TF Lüscher, prepared with the assistance of, F Cosentino, JA Beckman
Circulation, 2003Am Heart Assoc
oxygen species (such as superoxide anion) that inactivate NO to form peroxynitrite. 27, 28
Hyperglycemia may initiate this process by increasing superoxide anion production via the
mitochondrial electron transport chain. 28 Superoxide anion then promotes a cascade of
endothelial processes that engage increasing numbers of cellular elements to produce
oxygenderived free radicals. For example, superoxide anion activates protein kinase C
(PKC), 28 or visa versa, activation of PKC may contribute to superoxide generation. 29, 30 …
oxygen species (such as superoxide anion) that inactivate NO to form peroxynitrite. 27, 28 Hyperglycemia may initiate this process by increasing superoxide anion production via the mitochondrial electron transport chain. 28 Superoxide anion then promotes a cascade of endothelial processes that engage increasing numbers of cellular elements to produce oxygenderived free radicals. For example, superoxide anion activates protein kinase C (PKC), 28 or visa versa, activation of PKC may contribute to superoxide generation. 29, 30 Activation of PKC by glucose has been implicated in the regulation and activation of membrane-associated NAD (P) H-dependent oxidases and subsequent production of superoxide anion. 29 Indeed, the activity of NAD (P) H oxidase and levels of its protein subunits are increased in internal mammary arteries and saphenous veins of patients with diabetes. 31 Peroxynitrite, resulting from the interaction of NO and superoxide anion, oxidizes the NOS co-factor tetrahydrobiopterin. 32, 33 This uncouples the enzyme, which then preferentially increases superoxide anion production over NO production. 34, 35
Hence, a cascade effect occurs that results in ever-increasing production of superoxide anion and inactivation of NO. Mitochondrial production of superoxide anion also increases intracellular production of advanced glycation end products (AGEs). 28 These glycated proteins adversely affect cellular function both by affecting protein function and by activation of the receptor for AGEs (RAGE). 36, 37 AGEs, per se, increase production of oxygen-derived free radicals, and RAGE activation increases intracellular enzymatic superoxide oxide production. 38–40 In addition, increased superoxide anion production activates the hexosamine pathway, which diminishes NOS activation by protein kinase Akt. 41 These processes likely recruit extracellular xanthine oxidase, which further augments the oxidative stress. 42 Hyperglycemiainduced oxidative stress also may increase levels of asymmetric dimethylarginine, a competitive antagonist of NOS, by impairing the ability of dimethylarginine dimethylaminohydrolase to metabolize asymmetric dimethylarginine. 43 The concept that hyperglycemia-induced oxidative stress medi-
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