title: Pleiotropic effects of statins in distal human pulmonary artery smooth muscle cells.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Centre for Pharmacology and Therapeutics, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. o.ali@ic.ac.uk
authors: Omar F
authors: OF
authors: Ali
authors: Ellena J
authors: EJ
authors: Growcott
authors: Ghazwan S
authors: GS
authors: Butrous
authors: John
authors: J
authors: Wharton
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000069059:Atorvastatin; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D058685:Genetic Pleiotropy / Q000187:drug effects* / Q000502:physiology; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology*; D017035:Pravastatin / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D017035:Pravastatin