Abstract

Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2) regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo, treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC) with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro. Platelet-derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients.

Highlights

  • Pulmonary Hypertension (PH) is a pathophysiologic condition defined by a mean pulmonary arterial pressure .25 mmHg at rest [1] and is characterized by hypoxemia, exercise limitation, and in many cases, death [2]

  • We have previously found that delivery of fumagillin to bleomycin-injured mice decreased pulmonary fibrosis by a selective reduction in the number of accumulated fibroblasts in the lung parenchyma

  • Animals treated with fumagillin beginning 14 days after MCT lost significantly less weight at week 5 than MCT-injured animals treated with the vehicle

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Summary

Introduction

Pulmonary Hypertension (PH) is a pathophysiologic condition defined by a mean pulmonary arterial pressure .25 mmHg at rest [1] and is characterized by hypoxemia, exercise limitation, and in many cases, death [2]. The lesions of PH are characterized to various degrees, depending on the particular etiology, by the accumulation of endothelial cells, smooth muscle cells, and fibroblasts in the pulmonary vasculature (reviewed in [6]). Altered rates of proliferation and apoptosis in mesenchymal cells lead to thickened and narrowed vessels resulting in increased pulmonary arterial pressures and right ventricular strain [6]. In human PH (reviewed in [7]) and in experimental models of PH [3,8,9], smooth muscle and endothelial cells actively proliferate, leading to occlusion of the pulmonary arteries and the stigmata of PH. The currently available vasodilatory therapies for IPAH do enhance survival [10,11] but do not significantly address the root pathological lesions of PH: the accumulation of fibroblasts, smooth muscle and endothelial cells

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