基因敲除
血管平滑肌
缺氧诱导因子
细胞生长
血小板源性生长因子受体
细胞周期蛋白D1
细胞生物学
癌症研究
生物
小干扰RNA
生长因子
细胞周期蛋白D
下调和上调
化学
细胞
细胞周期
内分泌学
细胞培养
生物化学
转染
受体
细胞凋亡
基因
遗传学
平滑肌
作者
Kelly M. Schultz,Vanishree Murthy,Jeffrey B. Tatro,Donald E. Beasley
出处
期刊:American Journal of Physiology-lung Cellular and Molecular Physiology
[American Physiological Society]
日期:2009-06-01
卷期号:296 (6): L921-L927
被引量:24
标识
DOI:10.1152/ajplung.90393.2008
摘要
Arterial O 2 levels are thought to modulate vascular smooth muscle cell (VSMC) proliferation and vascular remodeling, but the mechanisms involved are poorly understood. Here, we tested the hypothesis that PHD2, a prolyl hydroxylase domain (PHD)-containing O 2 sensor, modulates growth factor-induced proliferative responses of human pulmonary artery SMC (HPASMC). We found that both PHD1 and PHD2 were robustly expressed by HPASMC, and inhibiting prolyl hydroxylase activity pharmacologically by using the nonselective dioxygenase inhibitor dimethyloxalylglycine (DMOG) inhibited proliferation and cyclin A expression induced by PDGF-AB or FGF-2. Specific knockdown of PHD2 using small interfering RNAs had similar effects. The inhibitory effects of DMOG and PHD2 knockdown on proliferation and cyclin A expression were seen under both normoxic (20% O 2 ) and moderately hypoxic (5% O 2 ) conditions, and PHD2 expression was not affected by O 2 level nor by stimulation with PDGF or FGF-2, indicating that the proproliferative influence of PHD2 does not involve alterations of its expression. Knockdown of PHD2 increased hypoxia-inducible factor (HIF)-1α expression, as expected, but we also found that HIF-1α knockdown abolished the inhibitory effect of PHD2 knockdown on PDGF-induced cyclin A expression. Therefore, we conclude that PHD2 promotes growth factor-induced responses of human VSMC, acting by HIF-1α-dependent mechanisms. Given the role of PHD2 as an oxygen sensor in mammalian cells, these results raise the possibility that PHD2 links VSMC proliferation to O 2 availability.
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