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Early treatment with fumagillin, an inhibitor of methionine aminopeptidase-2, prevents pulmonary hypertension in monocrotaline-injured rats

Kass, DJ and Rattigan, E and Kahloon, R and Loh, K and Yu, L and Savir, A and Markowski, M and Saqi, A and Rajkumar, R and Ahmad, F and Champion, HC (2012) Early treatment with fumagillin, an inhibitor of methionine aminopeptidase-2, prevents pulmonary hypertension in monocrotaline-injured rats. PLoS ONE, 7 (4).

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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. © 2012 Kass et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Kass, DJdjk61@pitt.eduDJK61
Rattigan, E
Kahloon, R
Loh, K
Yu, L
Savir, A
Markowski, M
Saqi, A
Rajkumar, R
Ahmad, F
Champion, HC
ContributionContributors NameEmailPitt UsernameORCID
Date: 16 April 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0035388
Schools and Programs: School of Medicine > Critical Care Medicine
Refereed: Yes
MeSH Headings: Aminopeptidases--antagonists & inhibitors; Aminopeptidases--genetics; Aminopeptidases--metabolism; Animals; Cell Proliferation--drug effects; Cells, Cultured; Cyclohexanes--administration & dosage; Disease Models, Animal; Fatty Acids, Unsaturated--administration & dosage; Gene Expression Regulation; Glycoproteins--antagonists & inhibitors; Glycoproteins--genetics; Glycoproteins--metabolism; Heart Ventricles--drug effects; Heart Ventricles--physiopathology; Hemodynamics; Humans; Hypertension, Pulmonary--chemically induced; Hypertension, Pulmonary--pathology; Hypertension, Pulmonary--prevention & control; Male; Monocrotaline--pharmacology; Myocytes, Cardiac--drug effects; Myocytes, Cardiac--metabolism; Myocytes, Smooth Muscle--cytology; Myofibroblasts--drug effects; Myofibroblasts--pathology; Platelet-Derived Growth Factor--genetics; Platelet-Derived Growth Factor--metabolism; Pulmonary Artery--cytology; Pulmonary Artery--drug effects; Rats; Rats, Sprague-Dawley; Sesquiterpenes--administration & dosage
Other ID: NLM PMC3324555
PubMed Central ID: PMC3324555
PubMed ID: 22509410
Date Deposited: 24 Sep 2012 20:27
Last Modified: 13 Oct 2017 18:55


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