[缺氧诱导因子-1α及其羟化酶在慢性阻塞性肺疾病患者肺动脉中的表达]

[The expression of hypoxia-inducible factor-1alpha and its hydroxylases in pulmonary arteries of patient with chronic obstructive pulmonary disease].

作者信息

Chen Yun-rong, Dai Ai-guo, Hu Rui-cheng, Kong Chun-chu

机构信息

Department of Respiratory Medicine, Hunan Institute of Gerontology, Hunan Province Geriatric Hospital, Changsha, China.

出版信息

Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012 May;28(3):234-8.

PMID:22860423

Abstract

OBJECTIVE

To observe the expression of hypoxia-inducible factor-lalpha subunit (HIF-1alpha), HIF prolyl hydroxylase domain-containing protein(PHDs) and factor inhibiting HIF-1(FIH) in pulmonary arteries of patient with chronic obstructive pulmonary disease (COPD).

METHODS

Pulmonary specimens were obtained from patients undergoing lobectomy for lung cancer, 12 had concurrent COPD (COPD group) and 14 without COPD (control group). The ratio of vascular wall area to total vascular area (WA%) and pulmonary artery media thickness (PAMT) was observed, and HIF-1alpha and its hydroxylases(PHD1, PHD2, PHD3, FIH) mRNA and protein were detected by in situ hybridization and immunohistochemistry respectively.

RESULTS

WA% and PAMT of COPD patients(50 microm +/- 9 microm, 40% +/- 5%, were statistically different from those of the control subjects (39 microm +/- 6 microm, 31% +/- 4%, P < 0.01). Relative quantification of mRNA and protein levels (absorbance, A) showed that HIF-lalpha mRNA and protein levels in COPD group (0.230 +/- 0.036,0.275 +/- 0.039) were statistically higher than those of the control subjects (0.174 +/- 0.029, 0.102 +/- 0.015, P < 0.01 ), and that the protein level increased more markedly. PHD1 mRNA in COPD subjects (0.180 +/- 0.030) was comparable to that in control group (0.191 +/- 0.029, P > 0.05); PHD2 and PHD3 mRNA levels in COPD (0.245 +/- 0.044, 0.252 +/- 0.023) were significantly higher than those in control group(0.182 +/- 0.028, 0.127 +/- 0.017, P < 0.01). On the other hand, in COPD subjects PHD1 protein (0.104 +/- 0.015) was significantly lower(P < 0.01), whereas PHD2 protein (0.274 +/- 0.044) was significantly higher(P < 0.01) than those in control group(0.209 +/- 0.023, 0.219+/- 0.043). As for PHD3 protein, no significant changes were observed between the two groups (0.161+/- 0.023 in COPD, 0.146 +/- 0.021 in control, P > 0.05). FIH mRNA and protein both showed no differences between the two groups. Linear correlation analysis showed that HIF1alpha protein was positively correlated with WA%, PAMT, PHD2 mRNA and protein, PHD3 mRNA, and that HIF1alpha protein was negatively correlated with PHD1 protein.

CONCLUSION

PHDs may be involved in the process of hypoxic pulmonary vascular remodeling in COPD via regulation of HIF-1alpha gene expression

摘要

目的

观察慢性阻塞性肺疾病（COPD）患者肺动脉中缺氧诱导因子-1α亚基（HIF-1α）、含HIF脯氨酰羟化酶结构域蛋白（PHD）和HIF-1抑制因子（FIH）的表达。

方法

取因肺癌行肺叶切除术患者的肺组织标本，其中12例合并COPD（COPD组），14例不合并COPD（对照组）。观察血管壁面积与总血管面积之比（WA%）及肺动脉中膜厚度（PAMT），分别采用原位杂交和免疫组化法检测HIF-1α及其羟化酶（PHD1、PHD2、PHD3、FIH）的mRNA和蛋白表达。

结果

COPD患者的WA%和PAMT（分别为50μm±9μm、40%±5%）与对照组（分别为39μm±6μm、31%±4%）相比，差异有统计学意义（P<0.01）。mRNA和蛋白水平的相对定量（吸光度，A）显示，COPD组HIF-1α的mRNA和蛋白水平（分别为0.230±0.036、0.275±0.039）显著高于对照组（分别为0.174±0.029、0.102±0.015，P<0.01），且蛋白水平升高更明显。COPD患者PHD1的mRNA（0.180±0.030）与对照组（0.191±0.029）相当（P>0.05）；COPD患者PHD2和PHD3的mRNA水平（分别为0.245±0.044、0.252±0.023）显著高于对照组（分别为0.182±0.028、0.127±0.017，P<0.01）。另一方面，COPD患者PHD1蛋白（0.104±0.015）显著低于对照组（0.209±0.023，P<0.01），而PHD2蛋白（0.274±0.044）显著高于对照组（0.219±0.043，P<0.01）。两组间PHD3蛋白无显著变化（COPD组为0.161±0.023，对照组为0.146±0.021，P>0.05）。两组间FIH的mRNA和蛋白均无差异。线性相关分析显示，HIF-1α蛋白与WA%、PAMT、PHD2的mRNA和蛋白、PHD3的mRNA呈正相关，与PHD1蛋白呈负相关。