Simvastatin Attenuates Smooth Muscle Neointimal Proliferation and Pulmonary Hypertension in Rats

Abstract

Hypertensive pulmonary vascular disease is characterized by abnor-prostanoids (7), which dilate reactive blood vessels and supmal proliferation of vascular endothelial and smooth muscle cells, press the growth of smooth muscle cells (8). Additional antileading to occlusion of pulmonary arterioles, pulmonary hypertenproliferative strategies for treatment of vascular occlusive sion, right ventricular failure, and death. Compounds with antiprodiseases are warranted (9). liferative effects on vascular endothelial and smooth muscle cells,Our group has previously demonstrated that antiproliferasuch as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductive drugs with no acute vasodilator properties effectively tase inhibitors, may prevent the development of experimental hyattenuate vascular remodeling with neointimal formation, pertensive pulmonary vascular disease. Pneumonectomized rats inpulmonary arterial hypertension, and right ventricular hyperjected with monocrotaline at 7 days develop severe hypertensive trophy in pneumonectomized, monocrotaline-injected rats (10, pulmonary vascular disease with neointimal formation. Rats were 11). The combination of pneumonectomy with monocrotaline randomized to receive either vehicle or treatment with the HMG-CoA reductase inhibitor simvastatin (2 mg/kg per day). By Day injection results in more severe pulmonary arterial hyperten-35, rats that received vehicle had higher mean pulmonary arterial sion (mean pulmonary arterial blood pressure [Ppa] ϭ 45 mm pressures (53 Ϯ 2 mm Hg) and right ventricular hypertrophy (right Hg) (10-12) than monocrotaline alone (Ppa ϭ 32 mm Hg) ventricle/[left ventricle plus septum] [RV/LVϩS] ϭ 0.78 Ϯ 0.09) (13-15). Importantly, only the combination of pneumonecthan rats in Group PMS 5-35 that received simvastatin from Day 5 to tomy with monocrotaline injection produces neointimal for-35 (mean pulmonary arterial pressure ϭ 27 Ϯ 3 mm Hg, RV/LVϩS ϭ mation and vascular obliteration of small pulmonary arteri-0.34 Ϯ 0.08; p р 0.001). Pulmonary vascular remodeling with neointioles that reproduces many of the pathological features of mal formation consisting of vascular smooth muscle cells was more human PPH (2, 9). severe in vehicle-treated rats (vascular occlusion score, 1.98 Ϯ 0.02) It is increasingly recognized that treatment with 3-hydroxthan in Group PMS 5-35 (vascular occlusion score, 0.59 Ϯ 0.46; p Ͻ ymethyl-3-methylglutaryl-coenzyme A (HMG-CoA) reduc-0.001). In addition, lung endothelial nitric oxide synthase gene expression was decreased in vehicle-treated animals but was re-tase inhibitors, statins, produces improvements in cardiovasstored toward normal levels in simvastatin-treated animals. Simcular outcomes that are incompletely explained by reductions vastatin attenuates monocrotaline-induced pulmonary vascular in cholesterol (16, 17). Statins exert direct antiinflammatory remodeling with neointimal formation, pulmonary arterial hyperand antiproliferative effects on the components of vascular tension, and right ventricular hypertrophy in rats...

Simvastatin Rescues Rats From Fatal Pulmonary Hypertension by Inducing Apoptosis of Neointimal Smooth Muscle Cells

“…16 We showed that simvastatin induced apoptosis of pathological vascular smooth muscle cells in vivo, in agreement with the finding that lipophilic statins induced apoptosis of vascular smooth muscle cells in vitro through downregu- lation of bcl-2 and rho prenylation. 26,27 We demonstrate here, as previously, 11 that simvastatin upregulated eNOS mRNA expression in vivo, and this may correlate with improved pulmonary endothelial function.…”

“…11 Here, we demonstrate that simvastatin conferred a 100% survival advantage on rats with established pulmonary hypertension, reversed established PAH, and was associated with reductions in pulmonary arterial neointimal occlusion, medial hypertrophy, and right ventricular hypertrophy. Neointimal pulmonary vascular occlusive lesions, consisting of proliferating smooth muscle cells and bearing similarities to the pathological lesions in human PPH, 4 are evident in rats after the combination of pneumonectomy with monocrotaline injection.…”

“…Neointimal pulmonary vascular occlusive lesions, consisting of proliferating smooth muscle cells and bearing similarities to the pathological lesions in human PPH, 4 are evident in rats after the combination of pneumonectomy with monocrotaline injection. 8,9,11,22,23 We hypothesize that a combination of compensatory lung growth after pneumonectomy, hemodynamic factors, and endothelial injury by monocrotaline pyrrole combine to produce this neointimal pulmonary vascular disease. 23 Delaying the injection of monocrotaline from 1 to 4 weeks after pneumonectomy slowed the rate of development of PAH and allowed us to document severe PAH before initiation of vehicle or rescue simvastatin treatment.…”

“…18,19 We recently demonstrated that simvastatin attenuates vascular smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized, monocrotaline-injected rats. 11 On the basis of our discovery of the efficacy of simvastatin in preventing neointimal pulmonary vascular disease in this model, we wanted to examine whether simvastatin could reverse established severe pulmonary hypertension after toxic injury and improve survival.…”

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

“…MCT is a naturally occurring pyrrolizidine alkaloid toxin found extracted from the plant species Crotalaria (Nishimura et al, 2002;Stenmark et al, 2009).…”