ROCK2 mediates the proliferation of pulmonary arterial endothelial cells induced by hypoxia in the development of pulmonary arterial hypertension

Qiao,Feng; Zou,Zhitian; Liu,Chunhui; Zhu,Xiaofeng; Wang,Xiaoqiang; Yang,Chengpeng; Jiang,Tengjiao; Chen,Ying

doi:10.3892/etm.2016.3214

ROCK2 mediates the proliferation of pulmonary arterial endothelial cells induced by hypoxia in the development of pulmonary arterial hypertension

Authors:
- Feng Qiao
- Zhitian Zou
- Chunhui Liu
- Xiaofeng Zhu
- Xiaoqiang Wang
- Chengpeng Yang
- Tengjiao Jiang
- Ying Chen
View Affiliations

Affiliations: Department of Thoracic Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China, Department of Intensive Care Unit, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China
Published online on: March 31, 2016 https://doi.org/10.3892/etm.2016.3214
Pages: 2567-2572

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

It has been reported that RhoA activation and Rho‑kinase (ROCK) expression are increased in chronic hypoxic lungs, and the long‑term inhibition of ROCK markedly improves the survival of patients with pulmonary arterial hypertension (PAH). However, whether Rho‑kinase α (ROCK2) participates in regulation of the growth of pulmonary arterial endothelial cells (PAECs) remains unknown. The aim of the present study was to investigate the effect of hypoxia on the proliferation of PAECs and the role of ROCK2 in the underlying mechanism. The results of western blotting and reverse transcription‑quantitative polymerase chain reaction analysis showed that hypoxia increased the activity and expression of ROCK2 in PAECs, and the stimulating effects of hypoxia on the proliferation of PAECs were attenuated by either the ROCK inhibitor Y27632 or transfection with ROCK2 small interfering RNA. Moreover, analysis of cyclin A and cyclin D1 mRNA expression indicated that ROCK2 mediates the cell cycle progression promoted by hypoxia. These results indicate that hypoxia promotes the proliferation of pulmonary arterial endothelial cells via activation of the ROCK2 signaling pathway.

View Figures

View References

1	Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaïci A, Weitzenblum E, Cordier JF, Chabot F, et al: Survival in patients with idiopathic, familial and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 122:156–163. 2010. View Article : Google Scholar : PubMed/NCBI
2	Fukumoto Y and Shimokawa H: Recent progress in the management of pulmonary hypertension. Circ J. 75:1801–1810. 2011. View Article : Google Scholar : PubMed/NCBI
3	Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, et al: Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 54(Suppl 1): S20–S31. 2009. View Article : Google Scholar : PubMed/NCBI
4	Shimokawa H and Rashid M: Development of Rho-kinase inhibitors for cardiovascular medicine. Trends Pharmacol Sci. 28:296–302. 2007. View Article : Google Scholar : PubMed/NCBI
5	Satoh K, Fukumoto Y and Shimokawa H: Rho-kinase: Important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol. 301:H287–H296. 2011. View Article : Google Scholar : PubMed/NCBI
6	Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K and Narumiya S: ROCK-I and ROCK-II, two isoforms of rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett. 392:189–193. 1996. View Article : Google Scholar : PubMed/NCBI
7	Chevrier V, Piel M, Collomb N, Saoudi Y, Frank R, Paintrand M, Narumiya S, Bornens M and Job D: The rho-associated protein kinase p160ROCK is required for centrosome positioning. J Cell Biol. 157:807–817. 2002. View Article : Google Scholar : PubMed/NCBI
8	Wei L, Roberts W, Wang L, Yamada M, Zhang S, Zhao Z, Rivkees SA, Schwartz RJ and Imanaka-Yoshida K: Rho kinases play an obligatory role in vertebrate embryonic organogenesis. Development. 128:2953–2962. 2001.PubMed/NCBI
9	Shimizu Y, Thumkeo D, Keel J, Ishizaki T, Oshima H, Oshima M, Noda Y, Matsumura F, Taketo MM and Narumiya S: ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles. J Cell Biol. 168:941–953. 2005. View Article : Google Scholar : PubMed/NCBI
10	Thumkeo D, Keel J, Ishizaki T, Hirose M, Nonomura K, Oshima H, Oshima M, Taketo MM and Narumiya S: Targeted disruption of the mouse rho-associated kinase 2 gene results in intrauterine growth retardation and fetal death. Mol Cell Biol. 23:5043–5055. 2003. View Article : Google Scholar : PubMed/NCBI
11	Medhora M, Chen Y, Gruenloh S, Harland D, Bodiga S, Zielonka J, Gebremedhin D, Gao Y, Falck JR, Anjaiah S and Jacobs ER: 20-HETE increases superoxide production and activates NAPDH oxidase in pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol. 294:L902–L911. 2008. View Article : Google Scholar : PubMed/NCBI
12	Ma J, Zhang L, Li S, Liu S, Ma C, Li W, Falck JR, Manthati VL, Reddy DS, Medhora M, et al: 8,9-Epoxyeicosatrienoic acid analog protects pulmonary artery smooth muscle cells from apoptosis via ROCK pathway. Exp Cell Res. 316:2340–2353. 2010. View Article : Google Scholar : PubMed/NCBI
13	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
14	Budhiraja R, Tuder RM and Hassoun PM: Endothelial dysfunction in pulmonary hypertension. Circulation. 109:159–165. 2004. View Article : Google Scholar : PubMed/NCBI
15	Pidgeon GP, Tamosiuniene R, Chen G, Leonard I, Belton O, Bradford A and Fitzgerald DJ: Intravascular thrombosis after hypoxia-induced pulmonary hypertension: Regulation by cyclooxygenase-2. Circulation. 110:2701–2707. 2004. View Article : Google Scholar : PubMed/NCBI
16	Abe K, Tawara S, Oi K, Hizume T, Uwatoku T, Fukumoto Y, Kaibuchi K and Shimokawa H: Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol. 48:280–285. 2006. View Article : Google Scholar : PubMed/NCBI
17	Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, Hattori T, Nakashima Y, Kaibuchi K, Sueishi K and Takeshit A: Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res. 94:385–393. 2004. View Article : Google Scholar : PubMed/NCBI
18	Doe Z, Fukumoto Y, Takaki A, Tawara S, Ohashi J, Nakano M, Tada T, Saji K, Sugimura K, Fujita H, et al: Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circ J. 73:1731–1739. 2009. View Article : Google Scholar : PubMed/NCBI
19	Oka M, Fagan KA, Jones PL and McMurtry IF: Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br J Pharmacol. 155:444–454. 2008. View Article : Google Scholar : PubMed/NCBI
20	Katula KS, Wright KL, Paul H, Surman DR, Nuckolls FJ, Smith JW, Ting JP, Yates J and Cogswell JP: Cyclin-dependent kinase activation and S-phase induction of the cyclin B1 gene are linked through the CCAAT elements. Cell Growth Differ. 8:811–820. 1997.PubMed/NCBI