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

Daniel J. Kass, Eileen Rattigan, Rehan Kahloon, Katrina Loh, Liyang Yu, Asaf Savir, Mark Markowski, Anjali Saqi, Revathi Rajkumar, Ferhaan Ahmad, Hunter C. Champion

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere35388
JournalPLoS One
Volume7
Issue number4
DOIs
StatePublished - 2012
Externally publishedYes

Fingerprint

monocrotaline
Monocrotaline
aminopeptidases
Pulmonary Hypertension
hypertension
methionine
Rats
lungs
Smooth Muscle Myocytes
rats
Muscle
smooth muscle
myocytes
Fibroblasts
Cells
Pulmonary Artery
pulmonary artery
Ventricular Remodeling
Endothelial cells
fibroblasts

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Early treatment with fumagillin, an inhibitor of methionine aminopeptidase-2, prevents pulmonary hypertension in monocrotaline-injured rats. / Kass, Daniel J.; Rattigan, Eileen; Kahloon, Rehan; Loh, Katrina; Yu, Liyang; Savir, Asaf; Markowski, Mark; Saqi, Anjali; Rajkumar, Revathi; Ahmad, Ferhaan; Champion, Hunter C.

In: PLoS One, Vol. 7, No. 4, e35388, 2012.

Research output: Contribution to journalArticle

Kass, DJ, Rattigan, E, Kahloon, R, Loh, K, Yu, L, Savir, A, Markowski, M, Saqi, A, Rajkumar, R, Ahmad, F & Champion, HC 2012, 'Early treatment with fumagillin, an inhibitor of methionine aminopeptidase-2, prevents pulmonary hypertension in monocrotaline-injured rats', PLoS One, vol. 7, no. 4, e35388. https://doi.org/10.1371/journal.pone.0035388
Kass, Daniel J. ; Rattigan, Eileen ; Kahloon, Rehan ; Loh, Katrina ; Yu, Liyang ; Savir, Asaf ; Markowski, Mark ; Saqi, Anjali ; Rajkumar, Revathi ; Ahmad, Ferhaan ; Champion, Hunter C. / Early treatment with fumagillin, an inhibitor of methionine aminopeptidase-2, prevents pulmonary hypertension in monocrotaline-injured rats. In: PLoS One. 2012 ; Vol. 7, No. 4.
@article{1947e537165a455d8b6ad6a27605f391,
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.",
author = "Kass, {Daniel J.} and Eileen Rattigan and Rehan Kahloon and Katrina Loh and Liyang Yu and Asaf Savir and Mark Markowski and Anjali Saqi and Revathi Rajkumar and Ferhaan Ahmad and Champion, {Hunter C.}",
year = "2012",
doi = "10.1371/journal.pone.0035388",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - Early treatment with fumagillin, an inhibitor of methionine aminopeptidase-2, prevents pulmonary hypertension in monocrotaline-injured rats

AU - Kass, Daniel J.

AU - Rattigan, Eileen

AU - Kahloon, Rehan

AU - Loh, Katrina

AU - Yu, Liyang

AU - Savir, Asaf

AU - Markowski, Mark

AU - Saqi, Anjali

AU - Rajkumar, Revathi

AU - Ahmad, Ferhaan

AU - Champion, Hunter C.

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84859587920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859587920&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0035388

DO - 10.1371/journal.pone.0035388

M3 - Article

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e35388

ER -