Yu Lunyin, Quinn Deborah A, Garg Hari G, Hales Charles A
Department of Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, USA.
Biochem Biophys Res Commun. 2006 Jul 14;345(4):1565-72. doi: 10.1016/j.bbrc.2006.05.060. Epub 2006 May 16.
The balance between cell proliferation and cell quiescence is regulated delicately by a variety of mediators, in which cyclin-dependent kinases (CDK) and CDK inhibitors (CDKI) play a very important role. Heparin which inhibits pulmonary artery smooth muscle cell (PASMC) proliferation increases the levels of two CDKIs, p21 and p27, although only p27 is important in inhibition of PASMC growth in vitro and in vivo. In the present study we investigated the expression profile of all the cell cycle regulating genes, including all seven CDKIs (p21, p27, p57, p15, p16, p18, and p19), in the lungs of mice with hypoxia-induced pulmonary hypertension. A cell cycle pathway specific gene microarray was used to profile the 96 genes involved in cell cycle regulation. We also observed the effect of heparin on gene expression. We found that (a) hypoxic exposure for two weeks significantly inhibited p27 expression and stimulated p18 activity, showing a 98% decrease in p27 and 81% increase in p18; (b) other CDKIs, p21, p57, p15, p16, and p19 were not affected significantly in response to hypoxia; (c) heparin treatment restored p27 expression, but did not influence p18; (d) ERK1/2 and p38 were mediators in heparin upregulation of p27. This study provides an expression profile of cell cycle regulating genes under hypoxia in mice with hypoxia-induced pulmonary hypertension and strengthens the previous finding that p27 is the only CDKI involved in heparin regulation of PASMC proliferation and hypoxia-induced pulmonary hypertension.
细胞增殖与细胞静止之间的平衡由多种介质精细调节，其中细胞周期蛋白依赖性激酶（CDK）和CDK抑制剂（CDKI）发挥着非常重要的作用。抑制肺动脉平滑肌细胞（PASMC）增殖的肝素可增加两种CDKI即p21和p27的水平，尽管在体外和体内仅p27对抑制PASMC生长具有重要作用。在本研究中，我们调查了低氧诱导的肺动脉高压小鼠肺中所有细胞周期调节基因的表达谱，包括所有七种CDKI（p21、p27、p57、p15、p16、p18和p19）。使用细胞周期途径特异性基因微阵列来分析参与细胞周期调节的96个基因。我们还观察了肝素对基因表达的影响。我们发现：（a）暴露于低氧两周显著抑制p27表达并刺激p18活性，p27降低98%，p18增加81%；（b）其他CDKI，即p21、p57、p15、p16和p19对低氧反应未受到显著影响；（c）肝素治疗可恢复p27表达，但不影响p18；（d）ERK1/2和p38是肝素上调p27的介质。本研究提供了低氧诱导的肺动脉高压小鼠在低氧状态下细胞周期调节基因的表达谱，并强化了先前的发现，即p27是参与肝素调节PASMC增殖和低氧诱导的肺动脉高压的唯一CDKI。
