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

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, mod...

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Published inDiabetes (New York, N.Y.) Vol. 51; no. 8; pp. 2648 - 2652
Main Authors CHRIST, Michael, BAUERSACHS, Johann, LIEBETRAU, Claudia, HECK, Marina, GÜNTHER, Andreas, WEHLING, Martin
Format Journal Article
LanguageEnglish
Published Alexandria, VA American Diabetes Association 01.08.2002
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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 micromol/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 micromol/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.
AbstractList 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 &lt; 0.05; measured by lucigenin-enhanced chemiluminescence). This effect was completely blocked after removal of the endothelium. Coincubation with 10 micromol/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 &lt; 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 micromol/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.
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 micromol/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 micromol/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.
Author CHRIST, Michael
GÜNTHER, Andreas
WEHLING, Martin
LIEBETRAU, Claudia
HECK, Marina
BAUERSACHS, Johann
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Keywords Endocrinopathy
Diabetes mellitus
Coronary artery
Cardiovascular disease
Glucose
Coenzyme
Endothelium
Vascular disease
NAD
Hyperoxides
Atherosclerosis
Atorvastatin
Complication
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SubjectTerms Animals
Associated diseases and complications
Atorvastatin
Biological and medical sciences
Coronary Vessels - drug effects
Coronary Vessels - enzymology
Coronary Vessels - physiology
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Endothelium, Vascular - drug effects
Endothelium, Vascular - enzymology
Endothelium, Vascular - physiology
Enzyme Activation - drug effects
Glucose - pharmacology
Heptanoic Acids - pharmacology
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
In Vitro Techniques
Medical sciences
Mevalonic Acid - pharmacology
NADH, NADPH Oxidoreductases - metabolism
NADPH Oxidases
Pyrroles - pharmacology
Superoxides - metabolism
Swine
Title 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
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