title: Early treatment with fumagillin, an inhibitor of methionine aminopeptidase-2, prevents Pulmonary Hypertension in monocrotaline-injured rats.
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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and the Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, Pittsburgh, Pennsylvania, United States of America. kassd2@upmc.edu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kass
authors.forename: Eileen
authors.initials: E
authors.lastname: Rattigan
authors.forename: Rehan
authors.initials: R
authors.lastname: Kahloon
authors.forename: Katrina
authors.initials: K
authors.lastname: Loh
authors.forename: Liyang
authors.initials: L
authors.lastname: Yu
authors.forename: Asaf
authors.initials: A
authors.lastname: Savir
authors.forename: Mark
authors.initials: M
authors.lastname: Markowski
authors.forename: Anjali
authors.initials: A
authors.lastname: Saqi
authors.forename: Revathi
authors.initials: R
authors.lastname: Rajkumar
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage*; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000008:administration & dosage
chemical_list: D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D006023:Glycoproteins; D010982:Platelet-Derived Growth Factor; D012717:Sesquiterpenes; D016686:Monocrotaline; C026211:fumagillin; D000626:Aminopeptidases; C489895:Metap2 protein, rat