Effect of YC-1 on hypoxia-induced vascular adventitial fibroblast proliferation and collagen synthesis <i>in vitro</i> _Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LIU Haichao , REN Juan , LI Long , XU Ruijuan ,  ZENG Qunli , HU Zhenhong

Department of Respiratory Medicine, Wuhan General Hospital of Chinese PLA, Wuhan, Hubei 430070, P. R. China;

Corresponding author：

ZENG Qunli, Email: lhc197628@163.com

Keywords：

3-(5'-Hydroxymethyl-2'-furyl)-1-benzylindazole; Hypoxia-inducible factor inhibitor; Adventitial fibroblast; Proliferation; Collagen synthesis; Hypoxia-inducible factor-1α; Transforming growth factor-β1

DOI：

10.7507/1671-6205.201804062

Video：

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ObjectiveTo investigate the effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), a hypoxia-inducible factor-1α (HIF-1α) inhibitor, on hypoxia induced rat pulmonary arterial adventitial fibroblasts (AFs) proliferation and collagen synthesis, and explore the molecular mechanism.MethodsUnder hypoxic condition, rat AFs were cultured in DMEM medium supplemented with 10% fetal bovine serum in vitro. The cells were divided into five groups, ie. a normoxia group, a hypoxia group and three hypoxia+YC-1 groups (treated with YC-1 at concentration of 0.01, 0.05 and 0.1 mmol/L, respectively). The cells proliferation was determined by MTT method. Collagen synthesis of AFs was measured by ³H-proline incorporation assay. The expression of HIF-1α in AFs in different conditions was measured by Western blot, and the mRNA expression of transforming growth factor-β1 (TGF-β1) was measured by reverse-transcription polymerase chain reaction.ResultsThe proliferation rate and the incorporation data of ³H-proline in the hypoxia group were significantly increased as compared with those in the control group (both P<0.01). YC-1 significantly reduced the proliferation rate and incorporation data of³H-proline induced by hypoxia in a dose-dependent manner. YC-1 could also down-regulate the expressions of HIF-1α and TGF-β1 mRNA significantly (both P<0.01). Compared with the hypoxia group, the expressions of HIF-1α and TGF-β1 mRNA decreased respectively by 65% and 61% in the hypoxia+YC-1 (0.1 mmol/L) group (bothP<0.01).ConclusionsYC-1 can inhibit hypoxia-induced AFs proliferation and collagen synthesis in a dose-dependent manner. The mechanism may relate to YC-1’s inhibitory effect on expressions of HIF-1α and TGF-β1 mRNA.

Citation： LIU Haichao, REN Juan, LI Long, XU Ruijuan, ZENG Qunli, HU Zhenhong. Effect of YC-1 on hypoxia-induced vascular adventitial fibroblast proliferation and collagen synthesis in vitro . Chinese Journal of Respiratory and Critical Care Medicine, 2018, 17(5): 504-508. doi: 10.7507/1671-6205.201804062 Copy

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2.	Stemark KR, Davie N, Frid M, et al. Role of the adventitia in pulmonary vascular remodeling. Physiology, 2006, 21(4): 134-145.
3.	Siow RC, Churchman AT. Adventitial growth factor signaling and vascular remodelling: potential of perivascular gene transfer from the outside-in. Cardiovasc Res, 2007, 75(4): 659-668.
4.	Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res, 2006, 99(7): 675-691.
5.	Plecitá-Hlavatá L, Tauber J, Li M et al. Constitutive reprogramming of fibroblast mitochondrial metabolism in pulmonary hypertension. Am J Respir Cell Mol Biol, 2016, 55(1): 47-57.
6.	Li M, Riddle S, Zhang H, et al. Metabolic reprogramming regulates the proliferative and inflammatory phenotype of adventitial fibroblasts in pulmonary hypertension through the transcriptional corepressor C-terminal binding protein-1. Circulation, 2016, 134(15): 1105-1121.
7.	Stenmark KR, Bouchey D, Nemenof R, et al. Hypoxia-induced pulmonary vascular remodeling: contribution of the adventitial fibroblasts. Physiol Res, 2000, 49(5): 503-517.
8.	McGrath JC, Deighan C, Briones AM, et al. New aspects of vascular remodelling: the involvement of all vascular cell types. Exp Physiol, 2005, 90(4): 469-475.
9.	Li Y, Zhang L, Wang X, et al. Elk-1-mediated 15-lipoxygenase expression is required for hypoxia-induced pulmonary vascular adventitial fibroblast dynamics. Acta Physiol (Oxf), 2016, 218(4): 276-289.
10.	Yuan W, Liu W, Cai H, et al. SB-431542, a specific inhibitor of the TGF-β type I receptor inhibits hypoxia-induced proliferation of pulmonary artery adventitial fibroblasts. Pharmazie, 2016, 71(2): 94-100.
11.	Fujiwara M, Muragaki Y, Ooshima A. Upregulation of transforming growth factor-beta1 and vascular endothelial growth factor in cultured keloid fibroblasts: relevance to angiogenic activity. Arch Dermatol Res, 2005, 297(4): 161-169.
12.	Zhang L, Chen Y, Li G, et al. TGF-β1/FGF-2 signaling mediates the 15-HETE-induced differentiation of adventitial fibroblasts into myofibroblasts. Lipids Health Dis, 2016, 15: 2.
13.	马绍骏, 蔡文玮, 盛净. 转化生长因子 β1 与体外血管外膜成纤维细胞的增殖和迁移. 中国组织工程研究与临床康复, 2011, 15(7): 1195-1198.
14.	Ryan ST, Koteliansky VE, Gotwals PJ, et al. Transforming growth factor-beta-dependent events in vascular remodeling following arterial injury. J Vasc Res, 2003, 40(1): 37-46.
15.	陈闻东, 楚玉峰, 刘建军, 等. RhoA-Rho 激酶信号转导通路参与 TGF-β1 诱导的血管外膜成纤维细胞表型转化为肌成纤维细胞. 生理学报, 2013, 65(2): 113-121.
16.	Liu Y, Ma C, Zhang Q, et al. The key role of transforming growth factor-beta receptor I and 15-lipoxygenase in hypoxia-induced proliferation of pulmonary artery smooth muscle cells. Int J Biochem Cell Biol, 2012, 44(7): 1184-1202.
17.	Liu Y, Cao YG, Sun SY, et al. Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways. Int J Biochem Cell Biol, 2016, 77(Pt A): 141-154.
18.	Lin S, Ma S, Lu P, et al. Effect of CTRP3 on activation of adventitial fibroblasts induced by TGF-β1 from rat aorta in vitro. Int J Clin Exp Pathol, 2014, 7(5): 2199-2208.
19.	Yung LM, Nikolic I, Paskin-Flerlage SD, et al. A selective transforming growth factor-β ligand trap attenuates pulmonary hypertension. Am J Respir Crit Care Med, 2016, 194(9): 1140-1151.
20.	Welsh DJ, Peacock AJ. Cellular responses to hypoxia in the pulmonary circulation. High Alt Med Biol, 2013, 14(2): 111-116.
21.	Li Q, Qiu YL, Mao M, et al. Antioxidant mechanism of Rutin on hypoxia-induced pulmonary arterial cell proliferation. Molecules, 2014, 19(11): 19036-19049.
22.	Zou RJ, Wang ZH, Wang CX, et al. Promoting vasa vasorum neovascularization of vein grafts extenuates hypoxia of the wall and its subsequent influence on intimal hyperplasia. Chin Med J (Engl), 2017, 130(11): 1327-1332.
23.	Ball MK, Waypa GB, Mungai PT, et al. Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. Am J Respir Crit Care Med, 2014, 189(3): 314-324.
24.	Wang L, Zhou Y, Li M, et al. Expression of hypoxia-inducible factor-1alpha, endothelin-1 and adrenomedullin in newborn rats with hypoxia-induced pulmonary hypertension. Exp Ther Med, 2014, 8(1): 335-339.
25.	Jiang YL, Dai AG, Li QF, et al. Hypoxia induces transforming growth factor- β1 gene expression in the pulmonary artery of rats via hypoxia-inducible factor-1α. Acta Biochim Biophys Sin (Shanghai), 2007, 39(1): 73-80.
26.	Tsui L, Fong TH, Wang IJ. YC-1 targeting of hypoxia-inducible factor-1alpha reduces RGG-5 cell viability and inhibits cell proliferation. Mol Vis, 2012, 18: 1594-1603.

1. Montani D, Günther S, Dorfmüller P, et al. Pulmonary arterial hypertension. Orphanet J Rare Dis, 2013, 8: 97.
2. Stemark KR, Davie N, Frid M, et al. Role of the adventitia in pulmonary vascular remodeling. Physiology, 2006, 21(4): 134-145.
3. Siow RC, Churchman AT. Adventitial growth factor signaling and vascular remodelling: potential of perivascular gene transfer from the outside-in. Cardiovasc Res, 2007, 75(4): 659-668.
4. Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res, 2006, 99(7): 675-691.
5. Plecitá-Hlavatá L, Tauber J, Li M et al. Constitutive reprogramming of fibroblast mitochondrial metabolism in pulmonary hypertension. Am J Respir Cell Mol Biol, 2016, 55(1): 47-57.
6. Li M, Riddle S, Zhang H, et al. Metabolic reprogramming regulates the proliferative and inflammatory phenotype of adventitial fibroblasts in pulmonary hypertension through the transcriptional corepressor C-terminal binding protein-1. Circulation, 2016, 134(15): 1105-1121.
7. Stenmark KR, Bouchey D, Nemenof R, et al. Hypoxia-induced pulmonary vascular remodeling: contribution of the adventitial fibroblasts. Physiol Res, 2000, 49(5): 503-517.
8. McGrath JC, Deighan C, Briones AM, et al. New aspects of vascular remodelling: the involvement of all vascular cell types. Exp Physiol, 2005, 90(4): 469-475.
9. Li Y, Zhang L, Wang X, et al. Elk-1-mediated 15-lipoxygenase expression is required for hypoxia-induced pulmonary vascular adventitial fibroblast dynamics. Acta Physiol (Oxf), 2016, 218(4): 276-289.
10. Yuan W, Liu W, Cai H, et al. SB-431542, a specific inhibitor of the TGF-β type I receptor inhibits hypoxia-induced proliferation of pulmonary artery adventitial fibroblasts. Pharmazie, 2016, 71(2): 94-100.
11. Fujiwara M, Muragaki Y, Ooshima A. Upregulation of transforming growth factor-beta1 and vascular endothelial growth factor in cultured keloid fibroblasts: relevance to angiogenic activity. Arch Dermatol Res, 2005, 297(4): 161-169.
12. Zhang L, Chen Y, Li G, et al. TGF-β1/FGF-2 signaling mediates the 15-HETE-induced differentiation of adventitial fibroblasts into myofibroblasts. Lipids Health Dis, 2016, 15: 2.
13. 马绍骏, 蔡文玮, 盛净. 转化生长因子 β1 与体外血管外膜成纤维细胞的增殖和迁移. 中国组织工程研究与临床康复, 2011, 15(7): 1195-1198.
14. Ryan ST, Koteliansky VE, Gotwals PJ, et al. Transforming growth factor-beta-dependent events in vascular remodeling following arterial injury. J Vasc Res, 2003, 40(1): 37-46.
15. 陈闻东, 楚玉峰, 刘建军, 等. RhoA-Rho 激酶信号转导通路参与 TGF-β1 诱导的血管外膜成纤维细胞表型转化为肌成纤维细胞. 生理学报, 2013, 65(2): 113-121.
16. Liu Y, Ma C, Zhang Q, et al. The key role of transforming growth factor-beta receptor I and 15-lipoxygenase in hypoxia-induced proliferation of pulmonary artery smooth muscle cells. Int J Biochem Cell Biol, 2012, 44(7): 1184-1202.
17. Liu Y, Cao YG, Sun SY, et al. Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways. Int J Biochem Cell Biol, 2016, 77(Pt A): 141-154.
18. Lin S, Ma S, Lu P, et al. Effect of CTRP3 on activation of adventitial fibroblasts induced by TGF-β1 from rat aorta in vitro. Int J Clin Exp Pathol, 2014, 7(5): 2199-2208.
19. Yung LM, Nikolic I, Paskin-Flerlage SD, et al. A selective transforming growth factor-β ligand trap attenuates pulmonary hypertension. Am J Respir Crit Care Med, 2016, 194(9): 1140-1151.
20. Welsh DJ, Peacock AJ. Cellular responses to hypoxia in the pulmonary circulation. High Alt Med Biol, 2013, 14(2): 111-116.
21. Li Q, Qiu YL, Mao M, et al. Antioxidant mechanism of Rutin on hypoxia-induced pulmonary arterial cell proliferation. Molecules, 2014, 19(11): 19036-19049.
22. Zou RJ, Wang ZH, Wang CX, et al. Promoting vasa vasorum neovascularization of vein grafts extenuates hypoxia of the wall and its subsequent influence on intimal hyperplasia. Chin Med J (Engl), 2017, 130(11): 1327-1332.
23. Ball MK, Waypa GB, Mungai PT, et al. Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. Am J Respir Crit Care Med, 2014, 189(3): 314-324.
24. Wang L, Zhou Y, Li M, et al. Expression of hypoxia-inducible factor-1alpha, endothelin-1 and adrenomedullin in newborn rats with hypoxia-induced pulmonary hypertension. Exp Ther Med, 2014, 8(1): 335-339.
25. Jiang YL, Dai AG, Li QF, et al. Hypoxia induces transforming growth factor- β1 gene expression in the pulmonary artery of rats via hypoxia-inducible factor-1α. Acta Biochim Biophys Sin (Shanghai), 2007, 39(1): 73-80.
26. Tsui L, Fong TH, Wang IJ. YC-1 targeting of hypoxia-inducible factor-1alpha reduces RGG-5 cell viability and inhibits cell proliferation. Mol Vis, 2012, 18: 1594-1603.

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Effect of YC-1 on hypoxia-induced vascular adventitial fibroblast proliferation and collagen synthesis in vitro

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