The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS.
HMG-CoA reductase inhibitors improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study was aimed to assess the protective effects of pravastatin (an HMG-CoA reductase inhibitor) against monocrotaline-induced pulmonary hypertension in rats. Pravastatin (PS, 10 mg/kg/day) or vehicle were given orally for 28 days to Wistar male rats injected or not with monocrotaline (MC, 60 mg/kg intraperitonealy) and treated or not by N(omega)-nitro-L-arginine methyl ester (L-NAME) 15 mg/kg/day. At 4 weeks, monocrotaline-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle+septum weight ratio (RV/LV+S), associated with a decrease in pulmonary artery dilation induced either by acetylcholine or sodium nitroprusside. Hypertensive pulmonary arteries exhibited an increase in medial thickness, medial wall area, endothelial cell apoptosis, and a decrease of endothelial nitric oxide synthase (eNOS) expression. Monocrotaline-rat lungs showed a significant decrease of eNOS expression (4080+/-27 vs 12189+/-761 arbitrary density units [ADU] for MC and control groups respectively, P<0.01) and a significant increase of cleaved caspase-3 expression by western blotting (Control=11628+/-2395 vs MC=2326+/-2243 ADU, P<0.05). A non-significant trend toward a reduced mortality was observed with pravastatin (relative risk of death = 0.33; 95% confidence interval [0.08-1.30], P= 0.12 for MC+PS vs MC groups). Pravastatine induced a protection against the development of the pulmonary hypertension (RVP in mmHg: 30+/-3 vs 45+/-4 and RV/LV+S: 0.46+/-0.04 vs 0.62+/-0.05 for MC+PS and MC groups respectively, P<0.05) and was associated with a significant reduction of MC-induced thickening (61+/-6 mum vs 81+/-3 mum for MC+PS and MC groups respectively, P= 0.01) of the medial wall of the small intrapulmonary arteries. Pravastatin partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (Emax=65+/-5% and 46+/-3% for MC+PS and MC group respectively, P<0.05) but had no effect on acetylcholine-induced pulmonary artery vasodilation in MC+L-NAME rats. It also prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells, as well as in the whole lung. Pravastatin reduces the development of monocrotaline-induced pulmonary hypertension and improves endothelium-dependent pulmonary artery relaxation, probably through a reduced apoptosis and a restored eNOS expression of endothelial cells.
Guerard
Pascal
P
Laboratory of Experimental Cardiovascular Physiopathology and Pharmacology (EA2979), IFR 100 Faculty of Medicine, BP 87900, 21000, Dijon, France. Pascal.Guerard@u-bourgogne.fr
Rakotoniaina
Zo
Z
Goirand
Françoise
F
Rochette
Luc
L
Dumas
Monique
M
Lirussi
Frederic
F
Bardou
Marc
M
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000473:pathology / Q000517:prevention & control; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D009599:Nitroprusside / Q000494:pharmacology; D011042:Poisons; D017035:Pravastatin / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D013534:Survival; D014665:Vasodilator Agents / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011042:Poisons; D014665:Vasodilator Agents; D009599:Nitroprusside; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III; D053148:Caspase 3; D017035:Pravastatin; D000109:Acetylcholine