Fluvastatin Inhibits Hypoxic Proliferation and p38 MAPK Activity in Pulmonary Artery Fibroblasts

Abstract

The earliest structural change in hypoxia-induced pulmonary hypertension is increased proliferation of adventitial fibroblasts. This fibroproliferative response occurs in acute and chronic hypoxic models, is dependent on p38 mitogen-activated protein (MAP) kinase activation, is selective for the pulmonary circulation, and would seem an important therapeutic target. Simvastatin attenuates pulmonary vascular remodeling in animal models, but additional information regarding mechanisms of action, differential antiproliferative effects and dose responses of available statins is required for appropriate clinical trial design. Our objectives were to determine the effects of statins on acute hypoxia-induced proliferation and p38 MAP kinase activation in pulmonary and systemic artery fibroblasts, to assess the effects of cholesterol intermediates, prenyltransferase and related inhibitors, and to determine the statin's mechanism of action. Atorvastatin, fluvastatin, and simvastatin inhibited adventitial fibroblast proliferation. At low doses (1 microM), this effect was selective for hypoxic (versus serum-induced) proliferation and was also selective for pulmonary (versus systemic) fibroblasts. Complete inhibition of hypoxia-induced p38 MAP kinase activity was achieved at this 1-microM dose. The lipophilic statins exhibited similar potency. The statin effect was reversed by geranylgeranyl pyrophosphate and mimicked by geranylgeranyl transferase and Rac1 inhibitors. Hypoxia-induced p38 MAP kinase activation and proliferation in pulmonary adventitial fibroblasts is dependent on a geranylgeranylated signaling protein, probably Rac1. One micromolar of fluvastatin exhibits a circulation- and stimulus-selective antiproliferative effect on pulmonary artery fibroblasts. The pharmacokinetics of fluvastatin would suggest that its antiproliferative effects may be useful in pulmonary hypertension associated with hypoxia.

Simvastatin and sildenafil combine to attenuate pulmonary hypertension

“…These GTPases regulate many cellular functions and couple membrane growth factor receptors to intracellular pathways that affect cell proliferation [6,7,9]. RhoA and its downstream mediator Rho-kinase have become an attractive target for the treatment of PAH [2,7].…”

The Ins and Outs of Small GTPase Rac1 in the Vasculature

“…Different statins inhibited adventitial fibroblast proliferation, and reduced p38 activation. The statin-mediated effect can be mimicked by inhibition of GGTase-1 or Rac1 (Carlin et al, 2007). Thus, as they did for VSMCs, statins inhibited proliferation via inhibition of GGTase-1 activity, probably preventing Rac1 activation.…”

“…Enhanced proliferation of adventitial fibroblasts is detrimental, such as in hypoxiainduced pulmonary hypertension. Excessive fibroblast proliferation under these conditions was caused by a Rac1/p38 signaling cascade (Carlin et al, 2007). Different statins inhibited adventitial fibroblast proliferation, and reduced p38 activation.…”

Pulmonary arterial hypertension and statins: an update

“…In contrast, Satoh et al [28] reported that pravastatin administration did not significantly reduce right ventricular systolic pressure and right ventricular/left ventricular and interventricular septal weight in rats, whereas both simvastatin and atorvastatin did. Fluvastatin was shown to reduce right ventricular pressure, right ventricular hypertrophy and muscularization of pulmonary artery, inhibit pulmonary adventitial fibroblast proliferation and restore endothelial dysfunction in rat models of hypoxiainduced PAH [30,48]. Similarly, rosuvastatin significantly ameliorated right ventricular hypertrophy, vascular remodelling and endothelial dysfunction, reduced right ventricular systolic pressure and suppressed peroxynitrite formation in rats with PAH [49,50].…”

“…Among them, simvastatin is the most well studied and was shown to attenuate PAH in both male and female rats by exerting several beneficial effects: reductions in mean PAP [23][24][25][26][27], right ventricular systolic pressure [28], right ventricular/left ventricular and interventricular septal weight [23,24,27,28] and right ventricular hypertrophy [25,26,29]; amelioration of pulmonary vascular remodelling (i.e. neointimal formation [29], muscularization and medial thickening [23,24,27]) via reduced proliferation and increased apoptosis of smooth muscle cells and endothelial cells [25,29], as well as inhibition of adventitial fibroblast proliferation [30]; improvement of oxidative status via upregulation of endothelial nitric oxide synthase (eNOS) [29,31,32] and reduction in reactive oxygen species production [26]; and inhibition of peribronchial and perivascular inflammation [32] via suppression of inflammatory genes expression (i.e. fos, jun and tumour necrosis factoralpha) [31].…”