Changes of hypoxia inducible factors in rats with high pulmonary blood flow-induced pulmonary artery hypertension

Yang LIU; Qing YU; Jing ZHANG; Mang SUN; yingying LIShang; Shengfen TU

doi:10.16016/j.1000-5404.201709088

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Changes of hypoxia inducible factors in rats with high pulmonary blood flow-induced pulmonary artery hypertension

Basic Medicine | 更新时间：2026-01-09

- Changes of hypoxia inducible factors in rats with high pulmonary blood flow-induced pulmonary artery hypertension
- Journal of Third Military Medical University Vol. 40, Issue 2, Pages: 116-121(2018)
- 作者机构：
  
  400014 重庆，重庆医科大学附属儿童医院麻醉科，儿童发育疾病研究教育部重点实验室，儿童发育重大疾病国家国际科技合作基地，儿科学重庆市重点实验室
- 作者简介：
- 基金信息：
  
  the National Clinical Key Discipline Construction Program of China(国卫办医函[2013]544号);the Project of Advanced Talent Pool of Chongqing Health and Family Planning Commission(2015HBRC007);the Natural Science Foundation of Chongqing(CSTC2012jjA10036)
- DOI：10.16016/j.1000-5404.201709088
  CLC： R322.35;R341;R543.2
- Received：12 September 2017，
  
  Revised：2017-11-28，
  
  Published：30 January 2018
- 稿件说明：
移动端阅览
Yang LIU, Qing YU, Jing ZHANG, et al. Changes of hypoxia inducible factors in rats with high pulmonary blood flow-induced pulmonary artery hypertension[J]. Journal of Third Military Medical University, 2018, 40(2): 116-121.
DOI：

Yang LIU, Qing YU, Jing ZHANG, et al. Changes of hypoxia inducible factors in rats with high pulmonary blood flow-induced pulmonary artery hypertension[J]. Journal of Third Military Medical University, 2018, 40(2): 116-121. DOI： 10.16016/j.1000-5404.201709088.

摘要

目的

观察缺氧诱导因子(hypoxia inducible factors，HIFs)在高肺血流性肺动脉高压大鼠肺组织的动态表达，探讨HIF-1α、HIF-2α在高肺血流性肺动脉高压形成过程中的作用。

方法

64只6周龄雄性健康SD大鼠采用随机数字法均分为假手术组与肺动脉高压组，肺动脉高压组大鼠通过腹主动脉-下腔静脉分流法建立高肺血流性肺动脉高压模型，在两组大鼠术后第4、8、12、16周测量平均肺动脉压力(mean pulmonary artery pressure

mPAP)、右心室肥厚指数(right ventricular hypertrophy index

RVHI)及肺血管形态学观察，Western blot检测肺组织HIF-1α、HIF-2α蛋白表达，RT-PCR检测HIF-1αmRNA、HIF-2αmRNA的表达。

结果

肺动脉高压组大鼠术后mPAP及RVHI随时间延长持续增高，肺动脉形态学变化与mPAP变化一致; 肺动脉高压组大鼠肺组织

HIF-1α、HIF-2α蛋白表达在术后随着时间的延长，均呈现先升高后下降的趋势，于术后8、12周明显高于同时间点对照组(

0.05);HIF-1αmRNA、HIF-2αmRNA的表达亦呈现先升高后下降的趋势，于术后8、12周明显高于同时间点对照组(

0.05)。

结论

HIF-1α和HIF-2α可能在大鼠高肺血流性肺动脉高压形成过程中的肺血管病变可逆阶段发挥了一过性的血管保护作用，但仍无法遏制肺动脉高压的形成。

Abstract

Objective

To evaluate the role of hypoxia inducible factors (HIF-1α and HIF-2α) in the pathogenesis of high blood flow-induced pulmonary artery hypertension (PAH) in rats.

Methods

Sixty-four healthy male SD rats (6 weeks) were randomly divided into sham-operated group and pulmonary hypertension group. A left-to-right shunt PAH model was established by creating an arterial-venous shunt between the abdominal aorta and the inferior vena cava in pulmonary hypertension group. The mean pulmonary arterial pressure (mPAP) and right ventricle hypertrophy index (RVHI) were measured and the vascular morphology was observed in 4

and 16 weeks after the operation. The mRNA and protein expressions of HIF-1α and HIF-2α in the lung tissues were determined using RT-PCR and Western blotting.

Results

Compared with the sham-operated rats

the rats with PAH showed a gradual increase of mPAP and RVHI over time

and significant increases of mPAP (

0.05) and RVHI (

0.05) occurred at 12 weeks and 16 weeks after the operation

respectively. The rats with PAH also exhibited severer pathological damages in the lungs than the sham-operated rats. Compared with the rats in the sham operation group

the rats with PHA showed significantly increased levels of HIF-1α and HIF-2α proteins at 8 and 12 weeks after the operation

respectively (

0.05)

with also significant increases in the mRNA levels of HIF-1α and HIF-2α (

0.05). In rats with PAH

the expressions of HIF-1α and HIF-2α at both protein and

mRNA levels showed an initial increase and a subsequent decrease over time after the operation.

Conclusion

In rats with high pulmonary blood flow-induced PAH

HIF-1α and HIF-2α may offer transient vascular protection in the reversible phase during the formation of pulmonary vascular lesions

but they are unable to prevent the occurrence of pulmonary hypertension.

关键词

Keywords

references

MYERS P O, TISSOT C, BEGHETTI M.Assessment of operability of patients with pulmonary arterial hypertension associated with congenital heart disease[J].Circ J, 2014, 78(1): 4-11.

STENMARK K R, FAGAN K A, FRID M G.Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms[J].Circ Res, 2006, 99(7): 675-691.DOI: 10.1161/01.RES.0000243584.45145.3f.

齐建光, 杜军保.肺动脉高压发病机制和诊治研究进展[J].中国循证儿科杂志, 2006, 1(1): 46-56.DOI: 10.3969/j.issn.1673-5501.2006.01.010.QI

J G, DU J B.Advances in pathogenesis, diagnosis and treatment of pulmonary hypertension[J].Chin J Evid Based Pediatr, 2006, 1(1): 46-56.DOI: 10.3969/j.issn.1673-5501.2006.01.010.

VEITH C, SCHERMULY R T, BRANDES R P, et al .Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension[J ] .J Physiol (Lond), 2016, 594(5): 1167-1177.DOI: 10.1113/JP270689.

GARCIA R, DIEBOLD S.Simple, rapid, and effective method of producing aortocaval shunts in the rat[J].Cardiovasc Res, 1990, 24(5): 430-432.DOI: 10.1093/cvr/24.5.430.

CALDER N-COLMENERO J, SANDOVAL Z RATE J, Beltr n G mez M.Pulmonary hypertension associated with congenital heart disease and Eisenmenger syndrome[J].Arch Cardiol Mex, 2015, 85(1): 32-49.DOI: 10.1016/j.acmx.2014.11.008.

GATZOULIS M A, BEGHETTI M, LANDZBERG M J, et al .Pulmonary arterial hypertension associated with congenital heart disease : Recent advances and future directions[J ] .Int J Cardiol, 2014, 177(2): 340-347.DOI: 10.1016/j.ijcard.2014.09.024.

HOEPER M M, BOGAARD H J, CONDLIFFE R, et al .Definitions and diagnosis of pulmonary hypertension[J ] .J Am Coll Cardiol, 2013, 6 2(25 Suppl): D42-D50.DOI: 10.1016/j.jacc.2013.10.032.

GALIÈ N, CORRIS P A, FROST A, et al .Updated treatment algorithm of pulmonary arterial hypertension[J ] .J Am Coll Cardiol, 2013, 62(25 Suppl): D60-D72.DOI: 10.1016/j.jacc.2013.10.031.

汪健春, 钟前进, 肖颖彬.bcl-2/bax表达在左向右分流型肺动脉高压肺血管重构中的作用[J].第三军医大学学报, 2009, 31(24): 2425-2428.

WANG J C, ZHONG Q J, XIAO Y B.Role of bcl-2 and bax expressions in pulmonary vascular remodeling of PAH rats secondary to left-right shunt CHD[J].Third Mil Med Univ, 2009, 31(24): 2425-2428.

L VY M, MAUREY C, CELERMAJER D S, et al .Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease[J ] .J Am Coll Cardiol, 2007, 49(7): 803-810.DOI: 10.1016/j.jacc.2006.09.049.

WAGENVOORT C A, WAGENVOORT N, DRAULANS-NO Y.Reversibility of plexogenic pulmonary arteriopathy following banding of the pulmonary artery[J].J Thorac Cardiovasc Surg, 1984, 87(6): 876-886.

VAN DER FEEN D E, BARTELDS B, DE BOER R A, et al .Pulmonary arterial hypertension in congenital heart disease: translational opportunities to study the reversibility of pulmonary vascular disease[J ] .Eur Heart J, 2017, 38(26): 2034-2041.DOI: 10.1093/eurheartj/ehx034.

YU A Y, FRID M G, SHIMODA L A, et al .Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung[J ] .Am J Physiol, 1998, 275(4 Pt 1): L818-L826.

LOBODA A, JOZKOWICZ A, DULAK J.HIF-1 and HIF-2 transcription factors--similar but not identical[J].Mol Cells, 2010, 29(5): 435-442.DOI: 10.1007/s10059-010-0067-2.

LOBODA A, JOZKOWICZ A, DULAK J.HIF-1 versus HIF-2--is one more important than the other[J].Vascul Pharmacol, 2012, 56(5-6): 245-251.DOI: 10.1016/j.vph.2012.02.006.

窦梦怡, 秦富忠, 李保.缺氧诱导因子在心脏重构和心力衰竭中的作用[J].中国循环杂志, 2015, 30(11): 1125-1127.DOI: 10.3969/j.issn.1000-3614.2015.11.022.DOU

M Y, QIN F Z, LI B.The role of hypoxia induced factor in cardiac reconstruction and heart failure[J].Chin Circul J, 2015, 30(11): 1125-1127.DOI: 11.3969/j.issn.1000-3614.2015.11.022.

FLORCZYK U, CZAUDERNA S , STACHURSKA A, et al .Opposite effects of HIF-1α and HIF-2α on the regulation of IL-8 expression in endothelial cells[J ] .Free Radic Biol Med, 2011, 51(10): 1882-1892.DOI: 10.1016/j.freeradbiomed.2011.08.023.

HOLMQUIST-MENGELBIER L, FREDLUND E, LÖFSTEDT T, et al .Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype[J ] .Cancer Cell, 2006, 10(5): 413-423.DOI: 10.1016/j.ccr.2006.08.026.

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