Pleiotropic effects of statins in distal human pulmonary artery smooth muscle cells
1 Centre for Pharmacology and Therapeutics, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
2 Novartis Institute for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK
3 Division of Cardiopulmonary Sciences, University of Kent, Research and Development Centre, Kent Institute of Medicine and Health Sciences, Parkwood Rd, Canterbury, Kent CT2 7PD, UK
Respiratory Research 2011, 12:137 doi:10.1186/1465-9921-12-137Published: 14 October 2011
Recent clinical data suggest statins have transient but significant effects in patients with pulmonary arterial hypertension. In this study we explored the molecular effects of statins on distal human pulmonary artery smooth muscle cells (PASMCs) and their relevance to proliferation and apoptosis in pulmonary arterial hypertension.
Primary distal human PASMCs from patients and controls were treated with lipophilic (simvastatin, atorvastatin, mevastatin and fluvastatin), lipophobic (pravastatin) and nitric-oxide releasing statins and studied in terms of their DNA synthesis, proliferation, apoptosis, matrix metalloproteinase-9 and endothelin-1 release.
Treatment of human PASMCs with selected statins inhibited DNA synthesis, proliferation and matrix metalloproteinase-9 production in a concentration-dependent manner. Statins differed in their effectiveness, the rank order of anti-mitogenic potency being simvastatin > atorvastatin > > pravastatin. Nevertheless, a novel nitric oxide-releasing derivative of pravastatin (NCX 6550) was effective. Lipophilic statins, such as simvastatin, also enhanced the anti-proliferative effects of iloprost and sildenafil, promoted apoptosis and inhibited the release of the mitogen and survival factor endothelin-1. These effects were reversed by mevalonate and the isoprenoid intermediate geranylgeranylpyrophosphate and were mimicked by inhibitors of the Rho and Rho-kinase.
Lipophilic statins exert direct effects on distal human PASMCs and are likely to involve inhibition of Rho GTPase signalling. These findings compliment some of the recently documented effects in patients with pulmonary arterial hypertension.