Attenuation of chronic hypoxic pulmonary hypertension by simvastatin
- 1 September 2003
- journal article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 285 (3), H938-H945
- https://doi.org/10.1152/ajpheart.01097.2002
Abstract
The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to improve multiple normal endothelial cell functions and inhibit vascular wall cell proliferation. We hypothesized that one such agent, simvastatin, would attenuate chronic hypoxic pulmonary hypertension. Male adult Sprague-Dawley rats were exposed (14 days) to normoxia (N), normoxia plus once-a-day administered simvastatin (20 mg/kg ip) (NS), hypoxia (10% inspired O2 fraction) (H), or hypoxia plus simvastatin (HS). Mean pulmonary artery pressure, measured in anesthetized, ventilated rats with an open-chest method, was reduced from 25 ± 2 mmHg in H to 18 ± 1 in HS ( P < 0.001) but did not reach normoxic values (12 ± 1 mmHg). Similarly, right ventricular/left ventricular plus interventricular septal weight was reduced from 0.53 ± 0.02 in the H group to 0.36 ± 0.02 in the HS group ( P < 0.001). The increased hematocrit in H (0.65 ± 0.02) was prevented by simvastatin treatment (0.51 ± 0.01, P < 0.001). Hematocrit was similar in N versus NS. Alveolar vessel muscularization and medial thickening of vessels 50–200 μM in diameter induced by hypoxia were also significantly attenuated in the HS animals. Lung endothelial nitric oxide synthase (eNOS) protein expression in the HS group was less than H ( P < 0.01) but was similar in N versus NS. We conclude that simvastatin treatment potently attenuates chronic hypoxic pulmonary hypertension and polycythemia in rats and inhibits vascular remodeling. Enhancement of lung eNOS expression does not appear to be involved in mediating this effect.Keywords
This publication has 45 references indexed in Scilit:
- Survival in Primary Pulmonary HypertensionCirculation, 2002
- Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathwayOncogene, 2002
- Modulation of COX-2 Expression by Statins in Human Aortic Smooth Muscle CellsPublished by Elsevier BV ,2001
- Mevastatin, an HMG-CoA Reductase Inhibitor, Reduces Stroke Damage and Upregulates Endothelial Nitric Oxide Synthase in MiceStroke, 2001
- Inhibition of sustained hypoxic vasoconstriction by Y‐27632 in isolated intrapulmonary arteries and perfused lung of the ratBritish Journal of Pharmacology, 2000
- 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
- Effects of chronic hypoxia and altered hemodynamics on endothelial nitric oxide synthase expression in the adult rat lung.JCI Insight, 1998
- Inhibition of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Blocks Hypoxia-mediated Down-regulation of Endothelial Nitric Oxide SynthaseJournal of Biological Chemistry, 1997
- Calcium mobilization and muscle contraction induced by acetylcholine in swine trachealisJournal of Biomedical Science, 1995
- Effect of Limonene and Sobrerol on Monocrotaline-lnduced Lung Alterations and Pulmonary HypertensionInternational Archives of Allergy and Immunology, 1995