Abstract
BackgroundRecent 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.MethodsPrimary 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.ResultsTreatment 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.ConclusionsLipophilic 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.
Highlights
Recent clinical data suggest statins have transient but significant effects in patients with pulmonary arterial hypertension
We sought to establish (1) the effect of statins on pulmonary artery smooth muscle cells (PASMCs) proliferation, apoptosis and production of factors implicated in the pathogenesis of PAH; (2) the anti-proliferative effect of statins when used in combination with established therapies for PAH and (3) the intermediates in the mevalonate pathway responsible for the action of statins
We have shown that statins exhibit several complementary effects in distal human PASMCs derived from patients with IPAH as well as other lung diseases
Summary
Recent clinical data suggest statins have transient but significant effects in patients with pulmonary arterial hypertension. It is recognised that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have beneficial cardiovascular effects beyond cholesterol lowering [1,2] These so-called pleiotropic effects depend principally on inhibiting the synthesis of the isoprenoid intermediates farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are essential for the post-translational processing, membrane translocation and activation of the Ras and Rho GTP-binding protein families. These GTPases regulate many cellular functions and couple membrane growth factor receptors to intracellular pathways that affect cell proliferation [3,4]. We sought to establish (1) the effect of statins on PASMC proliferation, apoptosis and production of factors (endothelin-1 and matrix metalloproteinase-9) implicated in the pathogenesis of PAH; (2) the anti-proliferative effect of statins when used in combination with established therapies for PAH and (3) the intermediates in the mevalonate pathway responsible for the action of statins
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