Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1.
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 hypoxia-stimulated proliferation of HPASMCs. We found 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.
Department of Pediatrics, University of Illinois at Chicago, 60612, USA.
Aarti
A
Raghavan
Guofei
G
Zhou
Qiyuan
Q
Zhou
Joyce Christina F
JC
Ibe
Ramaswamy
R
Ramchandran
Qiwei
Q
Yang
Harini
H
Racherla
Pradip
P
Raychaudhuri
J Usha
JU
Raj
D064127:Aurora Kinases; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D064127:Aurora Kinases; D051792:Basic Helix-Loop-Helix Proteins; D019926:Cyclin B; D019938:Cyclin D1; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017346:Protein Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C530104:CCND1 protein, human; C107585:FOXM1 protein, human; C497442:HIF1A protein, human