HMG-CoA Reductase Inhibitors Improve Endothelial Dysfunction in Normocholesterolemic Hypertension via Reduced Production of Reactive Oxygen Species
- 1 June 2001
- journal article
- other
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 37 (6), 1450-1457
- https://doi.org/10.1161/01.hyp.37.6.1450
Abstract
Abstract —3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) significantly reduce cardiovascular mortality associated with hypercholesterolemia. There is evidence that statins exert beneficial effects in part through direct effects on vascular cells independent of lowering plasma cholesterol. We characterized the effect of a 30-day treatment with atorvastatin in normocholesterolemic, spontaneously hypertensive rats (SHR). Systolic blood pressure was significantly decreased in atorvastatin-treated rats (184±5 versus 204±6 mm Hg for control). Statin therapy improved endothelial dysfunction, as assessed by carbachol-induced vasorelaxation in aortic segments, and profoundly reduced angiotensin II–induced vasoconstriction. Angiotensin type 1 (AT 1 ) receptor, endothelial cell NO synthase (ecNOS), and p22phox mRNA expression were determined with quantitative reverse transcription–polymerase chain reaction. Atorvastatin treatment downregulated aortic AT 1 receptor mRNA expression to 44±12% of control and reduced mRNA expression of the essential NAD(P)H oxidase subunit p22phox to 63±7% of control. Aortic AT 1 receptor protein expression was consistently decreased. Vascular production of reactive oxygen species was reduced to 62±12% of control in statin-treated SHR, as measured with lucigenin chemiluminescence assays. Accordingly, treatment of SHR with the AT 1 receptor antagonist fonsartan improved endothelial dysfunction and reduced vascular free-radical release. Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (138±7% of control) and an enhanced ecNOS activity in the vessel wall (209±46% of control). Treatment of SHR with atorvastatin causes a significant reduction of systolic blood pressure and a profound improvement of endothelial dysfunction mediated by a reduction of free radical release in the vasculature. The underlying mechanism could in part be based on the statin-induced downregulation of AT 1 receptor expression and decreased expression of the NAD(P)H oxidase subunit p22phox, because AT 1 receptor activation plays a pivotal role for the induction of this redox system in the vessel wall.Keywords
This publication has 21 references indexed in Scilit:
- Cerivastatin Suppresses Lipopolysaccharide-Induced ICAM-1 Expression through Inhibition of Rho GTPase in BAECBiochemical and Biophysical Research Communications, 2000
- Angiotensin II-induced superoxide anion generation in human vascular endothelial cells Role of membrane-bound NADH-/NADPH-oxidasesCardiovascular Research, 1999
- Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells.JCI Insight, 1998
- Coronary risk factors, endothelial function, and atherosclerosis: A reviewClinical Cardiology, 1997
- p22 Is a Critical Component of the Superoxide-generating NADH/NADPH Oxidase System and Regulates Angiotensin IIinduced Hypertrophy in Vascular Smooth Muscle CellsJournal of Biological Chemistry, 1996
- Fertility and General Reproduction Studies in Rats with the HMG-CoA Reductase Inhibitor, AtorvastatinFundamental and Applied Toxicology, 1996
- Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone.JCI Insight, 1996
- Prevention of Coronary Heart Disease with Pravastatin in Men with HypercholesterolemiaThe New England Journal of Medicine, 1995
- Cholesterol Reduction in Cardiovascular Disease — Clinical Benefits and Possible MechanismsThe New England Journal of Medicine, 1995
- Regulation of the mevalonate pathwayNature, 1990