Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1

Aarti Raghavan, Guofei Zhou, Qiyuan Zhou, Joyce Christina F. Ibe, Ramaswamy Ramchandran, Qiwei Yang, Harini Racherla, Pradip Raychaudhuri, J. Usha Raj

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease, and no effective treatments are available. Hypoxia-induced pulmonary artery remodeling, including smooth muscle cell proliferation, contributes to PAH, but the exact mechanisms underlying this abnormal process are largely undefined. The forkhead box M1 (FoxM1) transcription factor regulates cancer cell growth by modulating gene expression critical for cell cycle progression. Here, we report for the first time, to the best of our knowledge, a novel function of FoxM1 in the hypoxia-stimulated proliferation of human pulmonary artery smooth muscle cells (HPASMCs). Exposure to hypoxia caused a marked up-regulation of FoxM1 gene expression, mainly at the transcription level, and this induction correlated with HPASMC cell proliferation. The knockdown of FoxM1 inhibited the hypoxiastimulated proliferation of HPASMCs.Wefound that the knockdown of HIF-2α, but not HIF-1α, diminished FoxM1 induction in response to hypoxia. However, the knockdown of FoxM1 did not alter expression levels of HIF-2α or HIF-1α, suggesting that HIF-2α is an upstream regulator of FoxM1. Furthermore, the knockdown of FoxM1 prevented the hypoxia-induced expression of aurora A kinase and cyclin D1. Collectively, our results suggest that hypoxia induces FoxM1 gene expression in an HIF-2α-dependent pathway, thereby promoting HPASMC proliferation.

Original languageEnglish (US)
Pages (from-to)431-436
Number of pages6
JournalAmerican journal of respiratory cell and molecular biology
Volume46
Issue number4
DOIs
StatePublished - Apr 1 2012

Fingerprint

Cell proliferation
Smooth Muscle Myocytes
Muscle
Pulmonary Artery
Cell Proliferation
Lung
Gene expression
Gene Expression
Pulmonary Hypertension
Aurora Kinase A
Cells
Cyclin D1
Forkhead Transcription Factors
Cell growth
Transcription
Transcription Factors
Hypoxia
Cell Cycle
Up-Regulation
Growth

Keywords

  • Cell proliferation
  • FoxM1
  • HIF
  • Hypoxia
  • Pulmonary artery smooth muscle cells

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1. / Raghavan, Aarti; Zhou, Guofei; Zhou, Qiyuan; Ibe, Joyce Christina F.; Ramchandran, Ramaswamy; Yang, Qiwei; Racherla, Harini; Raychaudhuri, Pradip; Usha Raj, J.

In: American journal of respiratory cell and molecular biology, Vol. 46, No. 4, 01.04.2012, p. 431-436.

Research output: Contribution to journalArticle

Raghavan, A, Zhou, G, Zhou, Q, Ibe, JCF, Ramchandran, R, Yang, Q, Racherla, H, Raychaudhuri, P & Usha Raj, J 2012, 'Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1', American journal of respiratory cell and molecular biology, vol. 46, no. 4, pp. 431-436. https://doi.org/10.1165/rcmb.2011-0128OC
Raghavan, Aarti ; Zhou, Guofei ; Zhou, Qiyuan ; Ibe, Joyce Christina F. ; Ramchandran, Ramaswamy ; Yang, Qiwei ; Racherla, Harini ; Raychaudhuri, Pradip ; Usha Raj, J. / Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1. In: American journal of respiratory cell and molecular biology. 2012 ; Vol. 46, No. 4. pp. 431-436.
@article{2143b8c9ccdb4621b0c845b778372394,
title = "Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1",
abstract = "Pulmonary arterial hypertension (PAH) is a devastating disease, and no effective treatments are available. Hypoxia-induced pulmonary artery remodeling, including smooth muscle cell proliferation, contributes to PAH, but the exact mechanisms underlying this abnormal process are largely undefined. The forkhead box M1 (FoxM1) transcription factor regulates cancer cell growth by modulating gene expression critical for cell cycle progression. Here, we report for the first time, to the best of our knowledge, a novel function of FoxM1 in the hypoxia-stimulated proliferation of human pulmonary artery smooth muscle cells (HPASMCs). Exposure to hypoxia caused a marked up-regulation of FoxM1 gene expression, mainly at the transcription level, and this induction correlated with HPASMC cell proliferation. The knockdown of FoxM1 inhibited the hypoxiastimulated proliferation of HPASMCs.Wefound that the knockdown of HIF-2α, but not HIF-1α, diminished FoxM1 induction in response to hypoxia. However, the knockdown of FoxM1 did not alter expression levels of HIF-2α or HIF-1α, suggesting that HIF-2α is an upstream regulator of FoxM1. Furthermore, the knockdown of FoxM1 prevented the hypoxia-induced expression of aurora A kinase and cyclin D1. Collectively, our results suggest that hypoxia induces FoxM1 gene expression in an HIF-2α-dependent pathway, thereby promoting HPASMC proliferation.",
keywords = "Cell proliferation, FoxM1, HIF, Hypoxia, Pulmonary artery smooth muscle cells",
author = "Aarti Raghavan and Guofei Zhou and Qiyuan Zhou and Ibe, {Joyce Christina F.} and Ramaswamy Ramchandran and Qiwei Yang and Harini Racherla and Pradip Raychaudhuri and {Usha Raj}, J.",
year = "2012",
month = "4",
day = "1",
doi = "10.1165/rcmb.2011-0128OC",
language = "English (US)",
volume = "46",
pages = "431--436",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "4",

}

TY - JOUR

T1 - Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1

AU - Raghavan, Aarti

AU - Zhou, Guofei

AU - Zhou, Qiyuan

AU - Ibe, Joyce Christina F.

AU - Ramchandran, Ramaswamy

AU - Yang, Qiwei

AU - Racherla, Harini

AU - Raychaudhuri, Pradip

AU - Usha Raj, J.

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Pulmonary arterial hypertension (PAH) is a devastating disease, and no effective treatments are available. Hypoxia-induced pulmonary artery remodeling, including smooth muscle cell proliferation, contributes to PAH, but the exact mechanisms underlying this abnormal process are largely undefined. The forkhead box M1 (FoxM1) transcription factor regulates cancer cell growth by modulating gene expression critical for cell cycle progression. Here, we report for the first time, to the best of our knowledge, a novel function of FoxM1 in the hypoxia-stimulated proliferation of human pulmonary artery smooth muscle cells (HPASMCs). Exposure to hypoxia caused a marked up-regulation of FoxM1 gene expression, mainly at the transcription level, and this induction correlated with HPASMC cell proliferation. The knockdown of FoxM1 inhibited the hypoxiastimulated proliferation of HPASMCs.Wefound that the knockdown of HIF-2α, but not HIF-1α, diminished FoxM1 induction in response to hypoxia. However, the knockdown of FoxM1 did not alter expression levels of HIF-2α or HIF-1α, suggesting that HIF-2α is an upstream regulator of FoxM1. Furthermore, the knockdown of FoxM1 prevented the hypoxia-induced expression of aurora A kinase and cyclin D1. Collectively, our results suggest that hypoxia induces FoxM1 gene expression in an HIF-2α-dependent pathway, thereby promoting HPASMC proliferation.

AB - Pulmonary arterial hypertension (PAH) is a devastating disease, and no effective treatments are available. Hypoxia-induced pulmonary artery remodeling, including smooth muscle cell proliferation, contributes to PAH, but the exact mechanisms underlying this abnormal process are largely undefined. The forkhead box M1 (FoxM1) transcription factor regulates cancer cell growth by modulating gene expression critical for cell cycle progression. Here, we report for the first time, to the best of our knowledge, a novel function of FoxM1 in the hypoxia-stimulated proliferation of human pulmonary artery smooth muscle cells (HPASMCs). Exposure to hypoxia caused a marked up-regulation of FoxM1 gene expression, mainly at the transcription level, and this induction correlated with HPASMC cell proliferation. The knockdown of FoxM1 inhibited the hypoxiastimulated proliferation of HPASMCs.Wefound that the knockdown of HIF-2α, but not HIF-1α, diminished FoxM1 induction in response to hypoxia. However, the knockdown of FoxM1 did not alter expression levels of HIF-2α or HIF-1α, suggesting that HIF-2α is an upstream regulator of FoxM1. Furthermore, the knockdown of FoxM1 prevented the hypoxia-induced expression of aurora A kinase and cyclin D1. Collectively, our results suggest that hypoxia induces FoxM1 gene expression in an HIF-2α-dependent pathway, thereby promoting HPASMC proliferation.

KW - Cell proliferation

KW - FoxM1

KW - HIF

KW - Hypoxia

KW - Pulmonary artery smooth muscle cells

UR - http://www.scopus.com/inward/record.url?scp=84859395617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859395617&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2011-0128OC

DO - 10.1165/rcmb.2011-0128OC

M3 - Article

C2 - 22033266

AN - SCOPUS:84859395617

VL - 46

SP - 431

EP - 436

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 4

ER -