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HMG-CoA reductase inhibitor improves endothelial dysfunction in mineralocorticoid hypertension by inhibition of RhoA


Hermann, M (2003). HMG-CoA reductase inhibitor improves endothelial dysfunction in mineralocorticoid hypertension by inhibition of RhoA. American Journal of Hypertension, 16(5):A24.

Abstract

Statins reduce cardiovascular morbidity and mortality. These beneficial effects are not fully explained by their lipid-lowering action. As such, we investigated the impact of a new statin, rosuvastatin, on endothelial function, the key event in early atherogenesis, in an experimental model of normocholesterolemic hypertension. Hypertension was induced in Wistar-Kyoto rats by inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) with Glycyrrhizic acid (GA). 11β-HSD2 provides mineralocorticoid receptor specificity for aldosterone by metabolising glucocorticoids to their receptor inactive 11-dehydro derivatives. GA was added to the drinking water (3 g/L) for 21 days. From days 8 to 21 rosuvastatin (20 mg/kg/d) or placebo were added to chow. Endothelium-dependent and -independent relaxation of isolated aortic rings to acetylcholine (ACh, 10-10-10-5 mol/L) and sodium nitroprusside (SNP, 10-10-10-5 mol/L) was measured. In addition, vascular reactivity to endothelin-1 (ET-1; 10-10-10-7 mol/L) was investigated. ETA and ETB receptor mRNA expression was determined by RT-PCR and RhoA activity by a pull-down assay. Systolic blood pressure increased in rats treated with GA (175 vs 153 mmHg in controls; p<0.01). Endothelium-dependent relaxations to acetylcholine were blunted after GA treatment (p≤0.005 vs control), while the responses to SNP remained unchanged. Rosuvastatin normalized NO-mediated endothelium-dependent relaxation in hypertensive animals (p≤0.01 vs placebo), although blood pressure and cholesterol levels were not affected by the statin. Vascular reactivity to ET-1 was increased by GA (p<0.01 vs control), but not affected by rosuvastatin. ETB receptor mRNA decreased in the GA group (p<0.05 vs control) and was upregulated by rosuvastatin (p<0.005; GA+rosuvastatin vs GA), whereas ETA receptor mRNA upregulation in the GA group (p<0.01 vs control) was partially prevented by the statin. In addition, GA increased Rho-GTP binding (p≤0.05 vs control) which was prevented in both groups by rosuvastatin treatment (p≤0.01 control+rosuvastatin vs control and GA+rosuvastatin vs GA). These data for the first time show that HMG-CoA inhibition improves endothelial dysfunction in normocholesterolemic mineralocorticoid hypertension without affecting blood pressure or cholesterol levels by correction of a stimulated endothelin system

Abstract

Statins reduce cardiovascular morbidity and mortality. These beneficial effects are not fully explained by their lipid-lowering action. As such, we investigated the impact of a new statin, rosuvastatin, on endothelial function, the key event in early atherogenesis, in an experimental model of normocholesterolemic hypertension. Hypertension was induced in Wistar-Kyoto rats by inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) with Glycyrrhizic acid (GA). 11β-HSD2 provides mineralocorticoid receptor specificity for aldosterone by metabolising glucocorticoids to their receptor inactive 11-dehydro derivatives. GA was added to the drinking water (3 g/L) for 21 days. From days 8 to 21 rosuvastatin (20 mg/kg/d) or placebo were added to chow. Endothelium-dependent and -independent relaxation of isolated aortic rings to acetylcholine (ACh, 10-10-10-5 mol/L) and sodium nitroprusside (SNP, 10-10-10-5 mol/L) was measured. In addition, vascular reactivity to endothelin-1 (ET-1; 10-10-10-7 mol/L) was investigated. ETA and ETB receptor mRNA expression was determined by RT-PCR and RhoA activity by a pull-down assay. Systolic blood pressure increased in rats treated with GA (175 vs 153 mmHg in controls; p<0.01). Endothelium-dependent relaxations to acetylcholine were blunted after GA treatment (p≤0.005 vs control), while the responses to SNP remained unchanged. Rosuvastatin normalized NO-mediated endothelium-dependent relaxation in hypertensive animals (p≤0.01 vs placebo), although blood pressure and cholesterol levels were not affected by the statin. Vascular reactivity to ET-1 was increased by GA (p<0.01 vs control), but not affected by rosuvastatin. ETB receptor mRNA decreased in the GA group (p<0.05 vs control) and was upregulated by rosuvastatin (p<0.005; GA+rosuvastatin vs GA), whereas ETA receptor mRNA upregulation in the GA group (p<0.01 vs control) was partially prevented by the statin. In addition, GA increased Rho-GTP binding (p≤0.05 vs control) which was prevented in both groups by rosuvastatin treatment (p≤0.01 control+rosuvastatin vs control and GA+rosuvastatin vs GA). These data for the first time show that HMG-CoA inhibition improves endothelial dysfunction in normocholesterolemic mineralocorticoid hypertension without affecting blood pressure or cholesterol levels by correction of a stimulated endothelin system

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Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:150 Psychology
Language:English
Date:1 May 2003
Deposited On:20 Sep 2018 13:29
Last Modified:31 Jul 2020 01:53
Publisher:Nature Publishing Group
ISSN:0895-7061
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1016/s0895-7061(03)00137-7
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicenceoxford101016S0895706103001377 (Library Catalogue)

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