Compounds that lead to a reversal of established pulmonary vascular disease might provide a cure for pulmonary arterial hypertension. The aim of this study was to examine the effect of simvastatin (2mg/kg/day) in rats with established pulmonary arterial hypertension (PAH).
Four weeks after pneumonectomy rats received monocrotaline 60mg/kg by intraperitoneal injection. Severe PAH develops 11 weeks after pneumonectomy (mean pulmonary artery pressure, mPAP = 42 vs. 17mmHg in normal rats). Rats were randomized to receive simvastatin or control solution by gavage from week 11.
All rats that received control solution died at week 13. When rats with severe PAH received simvastatin (2 mg/kg/day, by gavage) from week 11, there was 100% survival, reversal of PAH at week 13 (mPAP = 36mmHg) and week 17 (mPAP = 24mmHg). Simvastatin therapy was associated with reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated inflammatory genes fos, jun, and TNF-α, and upregulated cell cycle inhibitor p27Kip1 and endothelial Nitric oxide synthase (eNOS).
Simvastatin reverses monocrotaline-induced pulmonary arterial hypertension and confers a 100% survival advantage.
Simvastatin is a candidate therapy for human pulmonary hypertension. Study of the effect of simvastatin in humans is indicated.
J.L. Faul, Merck, Grant monies. Speaker’s forum.