RESUMO
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.
Assuntos
Pleiotropia Genética/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Artéria Pulmonar/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Atorvastatina , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Pleiotropia Genética/fisiologia , Ácidos Heptanoicos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiologia , Pravastatina/farmacologia , Artéria Pulmonar/citologia , Artéria Pulmonar/fisiologia , Pirróis/farmacologia , Sinvastatina/farmacologiaRESUMO
Culture-negative endocarditis (CNE) presents physicians with diagnostic and treatment challenges. Postpartum endocarditis is rare and usually culture negative. Empirical antimicrobial regimes lead to the risk of aggressive treatment with potentially toxic drugs. This paper presents a case of postpartum CNE, discussing the issues of diagnosis and treatment. European and American guidelines for CNE are then reviewed and compared.
