Rac1 mediates HMGB1‑induced hyperpermeability in pulmonary microvascular endothelial cells via MAPK signal transduction

Shao,Min; Tang,Song‑Tao; Liu,Bao; Zhu,Hua‑Qing

doi:10.3892/mmr.2015.4521

Rac1 mediates HMGB1‑induced hyperpermeability in pulmonary microvascular endothelial cells via MAPK signal transduction

Authors:
- Min Shao
- Song‑Tao Tang
- Bao Liu
- Hua‑Qing Zhu
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Affiliations: Department of Critical Care Medicine, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui 230001, P.R. China, Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China
Published online on: November 6, 2015 https://doi.org/10.3892/mmr.2015.4521
Pages: 529-535

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Abstract

The pathology of acute respiratory distress syndrome (ARDS) is closely associated with the failure of alveolar‑capillary barrier integrity and alveolar filling by high protein pulmonary edema, resulting from hyperpermeability. High mobility group box 1 (HMGB1) is a novel late mediator of sepsis, which is specifically involved in endotoxin‑induced acute lung injury and sepsis‑associated lethality. Although the role of HMGB1 in endothelial cell cytoskeletal rearrangement and vascular permeability have been investigated preliminarily, the molecular mechanisms remain to be fully elucidated. As the ras‑related C3 botulinum toxin substrate 1 (Rac1) gene is important role in regulating microvascular barrier maintenance, the present study was designed to determine whether Rac1 is involved in HMGB1‑induced hyperpermeability in pulmonary microvascular endothelial cells (PMVECs). The results of the present study demonstrated that HMGB1 induced dose and time‑dependent decreases in transendothelial electrical resistance (TER). Notably, HMGB1 induced a dose‑dependent increase in the activity and expression levels of Rac1. Using small interfering RNA and an agonist of Rac1, the present study demonstrated that Rac1 was a novel factor mediating the HMGB1‑induced decrease in TER via extracellular signal‑regulated kinase and p38 mitogen‑activated protein kinase (MAPK) activation. These data suggested that Rac1 is involved in HMGB1‑induced hyperpermeability in PMVECs via MAPK signal transduction.

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1	Ware LB: Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Semin Respir Crit Care Med. 27:337–349. 2006. View Article : Google Scholar : PubMed/NCBI
2	Dudek SM and Garcia JG: Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol (1985). 91:1487–1500. 2001.
3	Beckers CM, van Hinsbergh VW and van Nieuw Amerongen GP: Driving Rho GTPase activity in endothelial cells regulates barrier Integrity. Thromb Haemost. 103:40–55. 2010. View Article : Google Scholar : PubMed/NCBI
4	Waschke J, Baumgartner W, Adamson RH, Zeng M, Aktories K, Barth H, Wilde C, Curry FE and Drenckhahn D: Requirement of Rac activity for maintenance of capillary endothelial barrier properties. Am J Physiol Heart Circ Physiol. 286:H394–H401. 2004. View Article : Google Scholar
5	Adamson RH, Ly JC, Sarai RK, Lenz JF, Altangerel A, Drenckhahn D and Curry FE: Epac/Rap1 pathway regulates microvascular hyperpermeability induced by PAF in rat mesentery. Am J Physiol Heart Circ Physiol. 294:H1188–H1196. 2008. View Article : Google Scholar : PubMed/NCBI
6	Birukova AA, Fu P, Xing J and Birukov KG: Rap1 mediates protective effects of iloprost against ventilator-induced lung injury. J Appl Physiol (1985). 107:1900–1910. 2009. View Article : Google Scholar
7	Spindler V, Schlegel N and Waschke J: Role of GTPases in control of microvascular permeability. Cardiovasc Res. 87:243–253. 2010. View Article : Google Scholar : PubMed/NCBI
8	Wang Y, Zang QS, Liu Z, Wu Q, Maass D, Dulan G, Shaul PW, Melito L, Frantz DE, Kilgore JA, et al: Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species. Am J Physiol Cell Physiol. 301:C695–C704. 2011. View Article : Google Scholar : PubMed/NCBI
9	Wojciak-Stothard B, Tsang LY and Haworth SG: Rac and Rho play opposing roles in the regulation of hypoxia/reoxygenation-induced permeability changes in pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol. 288:L749–L760. 2005. View Article : Google Scholar
10	van Wetering S, van Buul JD, Quik S, Mul FP, Anthony EC, ten Klooster JP, Collard JG and Hordijk PL: Reactive oxygen species mediate Rac-induced loss of cell-cell adhesion in primary human endothelial cells. J Cell Sci. 115:1837–1846. 2002.PubMed/NCBI
11	Chen W, Pendyala S, Natarajan V, Garcia JG and Jacobson JR: Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition. Am J Physiol Lung Cell Mol Physiol. 295:L575–L583. 2008. View Article : Google Scholar : PubMed/NCBI
12	Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, et al: HMG-1 as a late mediator of endotoxin lethality in mice. Science. 285:248–251. 1999. View Article : Google Scholar : PubMed/NCBI
13	Kim DC, Lee W and Bae JS: Vascular anti-inflammatory effects of curcumin on HMGB1-mediated responses in vitro. Inflamm Res. 60:1161–1168. 2011. View Article : Google Scholar : PubMed/NCBI
14	Gao M, Hu Z, Zheng Y, Zeng Y, Shen X, Zhong D and He F: Peroxisome proliferator-activated receptor γ agonist troglitazone inhibits high mobility group box 1 expression in endothelial cells via suppressing transcriptional activity of nuclear factor κB and activator protein 1. Shock. 36:228–234. 2011. View Article : Google Scholar : PubMed/NCBI
15	Wolfson RK, Chiang ET and Garcia JG: HMGB1 induces human lung endothelial cell cytoskeletal rearrangement and barrier disruption. Microvasc Res. 81:189–197. 2011. View Article : Google Scholar
16	Kim JY, Park JS, Strassheim D, Douglas I, Diaz del Valle F, Asehnoune K, Mitra S, Kwak SH, Yamada S, Maruyama I, et al: HMGB1 contributes to the development of acute lung injury after hemorrhage. Am J Physiol Lung Cell Mol Physiol. 288:L958–L965. 2005. View Article : Google Scholar : PubMed/NCBI
17	Wojciak-Stothard B and Ridley AJ: Rho GTPases and the regulation of endothelial permeability. Vascul Pharmacol. 39:187–199. 2002. View Article : Google Scholar
18	Wójciak-Stothard B, Potempa S, Eichholtz T and Ridley AJ: Rho and Rac but not Cdc42 regulate endothelial cell permeability. J Cell Sci. 114:1343–1355. 2001.PubMed/NCBI
19	Baumer Y, Spindler V, Werthmann RC, Bünemann M and Waschke J: Role of Rac 1 and cAMP in endothelial barrier stabilization and thrombin-induced barrier breakdown. J Cell Physiol. 220:716–726. 2009. View Article : Google Scholar : PubMed/NCBI
20	Shao M, Yue Y, Sun GY, You QH, Wang N and Zhang D: Caveolin-1 regulates Rac1 activation and rat pulmonary micro-vascular endothelial hyperpermeability induced by TNF-α. PLoS One. 8:e55212013. View Article : Google Scholar
21	Guo XH, Huang QB, Chen B, Wang SY, Li Q, Zhu YJ, Hou FF, Fu N, Brunk UT and Zhao M: Advanced glycation end products induce actin rearrangement and subsequent hyperpermeability of endothelial cells. APMIS. 114:874–883. 2006. View Article : Google Scholar
22	Lin CH, Shih CH, Tseng CC, Yu CC, Tsai YJ, Bien MY and Chen BC: CXCL12 induces connective tissue growth factor expression in human lung fibroblasts through the Rac1/ERK, JNK, and AP-1 pathways. PLoS One. 9:e1047462014. View Article : Google Scholar : PubMed/NCBI