Teng Xingwu, Li Dechun, Champion Hunter C, Johns Roger A
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Blalock 1415, 600 N Wolfe St, Baltimore, Md 21287, USA.
Circ Res. 2003 May 30;92(10):1065-7. doi: 10.1161/01.RES.0000073999.07698.33. Epub 2003 Apr 24.
In a mouse chronic hypoxia model of pulmonary hypertension, we discovered a novel hypoxia-inducible gene in lung, FIZZ1/RELMalpha, first through a cDNA array analysis and then confirmed by RT-PCR. Western blot and immunohistochemistry revealed that its expression was induced by hypoxia only in lung. The hypoxia-upregulated gene expression was located in the pulmonary vasculature, bronchial epithelial cells, and type II pneumocytes. 3H-thymidine incorporation demonstrated that the recombinant protein stimulated rat pulmonary microvascular smooth muscle cell (RPSM) proliferation dose-dependently ranging from 3.3x10(-9) to 3.3x10(-8) mol/L. Therefore, we renamed this gene as hypoxia-induced mitogenic factor (HIMF). HIMF strongly activated Akt phosphorylation. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (10 micromol/L) inhibited HIMF-activated Akt phosphorylation. It also inhibited HIMF-stimulated RPSM proliferation. Thus, the PI3K/Akt pathway, at least in part, mediates the proliferative effect of HIMF. Further studies showed that HIMF had angiogenic and vasoconstrictive properties. HIMF increased pulmonary arterial pressure and vascular resistance more potently than either endothelin-1 or angiotensin II.
在小鼠肺动脉高压慢性缺氧模型中，我们首先通过cDNA阵列分析在肺中发现了一个新的缺氧诱导基因FIZZ1/RELMα，随后通过逆转录聚合酶链反应（RT-PCR）进行了确认。蛋白质免疫印迹法和免疫组织化学显示，其表达仅在肺中由缺氧诱导。缺氧上调的基因表达位于肺血管、支气管上皮细胞和II型肺泡上皮细胞中。3H-胸腺嘧啶核苷掺入实验表明，重组蛋白在3.3×10（-9）至3.3×10（-8）mol/L范围内剂量依赖性地刺激大鼠肺微血管平滑肌细胞（RPSM）增殖。因此，我们将该基因重新命名为缺氧诱导促有丝分裂因子（HIMF）。HIMF强烈激活Akt磷酸化。磷脂酰肌醇3-激酶（PI3K）抑制剂LY294002（10 μmol/L）抑制HIMF激活的Akt磷酸化。它还抑制HIMF刺激的RPSM增殖。因此，PI3K/Akt途径至少部分介导了HIMF的增殖作用。进一步研究表明，HIMF具有血管生成和血管收缩特性。HIMF比内皮素-1或血管紧张素II更有效地增加肺动脉压和血管阻力。
