Glucose Increases Endothelial-Dependent Superoxide Formation in Coronary Arteries by NAD(P)H Oxidase Activation

Glucose Increases Endothelial-Dependent Superoxide Formation in Coronary Arteries by NAD(P)H Oxidase Activation Attenuation by the 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Atorvastatin Michael Christ 1 2 , Johann Bauersachs 3 , Claudia Liebetrau 3 , Marina Heck 1 , Andreas Günther 1 and Martin Wehling 1 1 Institute of Clinical Pharmacology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Heidelberg, Germany 2 Klinik für Innere Medizin, Kardiologie, Philipps University Marburg, Marburg, Germany 3 Department of Medicine, University of Würzburg, Würzburg, Germany Abstract Increased vascular superoxide anion (O 2 − ) formation is essentially involved in the pathophysiology of atherosclerosis. Chronic hyperglycemia induces endothelial dysfunction, probably due to increased formation of reactive oxygen intermediates. However, little is known about the localization, modulators, and molecular mechanisms of vascular O 2 − formation during hyperglycemia. In porcine coronary segments, high glucose significantly increased O 2 − formation (1,703.5 ± 394.9 vs. 834.1 ± 91.7 units/mg for control, n = 64, P < 0.05; measured by lucigenin-enhanced chemiluminescence). This effect was completely blocked after removal of the endothelium. Coincubation with 10 μmol/l atorvastatin, a lipophilic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, attenuated basal and glucose-induced O 2 − formation (328.1 ± 46.5 and 332.8 ± 50.3 units/mg, P < 0.05 vs. without atorvastatin). Incubation with mevalonic acid reversed this effect. High glucose increased mRNA expression of the oxidase subunit p22 phox , which was blocked by 10 μmol/l atorvastatin, whereas expression of gp91 phox was unchanged. In conclusion, glucose-induced increase of vascular O 2 − formation is endothelium dependent and is probably mediated by increased p22 phox subunit expression. Beneficial effects of statins in diabetic patients may be explained in part by attenuation of vascular O 2 − formation independent of lipid lowering. Footnotes Address correspondence and reprint requests to Michael Christ, MD, Klinik für Innere Medizin, Kardiologie, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. E-mail: christ_michael{at}yahoo.de . Received for publication 12 May 2000 and accepted in revised form 13 May 2002. eNOs, endothelial nitric oxide synthase; G3PDH, glyceraldehyde-3-phosphate-dehydrogenase; HMG, hydroxymethylglutaryl; LMWG, low molecular weight GTP