Galectin-3-induced oxidized low-density lipoprotein promotes the phenotypic transformation of vascular smooth muscle cells

Tian,Lei; Chen,Kan; Cao,Jiatian; Han,Zhihua; Gao,Lin; Wang,Yue; Fan,Yuqi; Wang,Changqian

doi:10.3892/mmr.2015.4075

Galectin-3-induced oxidized low-density lipoprotein promotes the phenotypic transformation of vascular smooth muscle cells

Authors:
- Lei Tian
- Kan Chen
- Jiatian Cao
- Zhihua Han
- Lin Gao
- Yue Wang
- Yuqi Fan
- Changqian Wang
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Affiliations: Department of Cardiology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, P.R. China
Published online on: July 13, 2015 https://doi.org/10.3892/mmr.2015.4075
Pages: 4995-5002
Copyright: © Tian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Oxidized low-density lipoprotein (oxLDL) is involved in the pathological phenotypic transformation of vascular smooth muscle cells in atherosclerosis. Galectin‑3 also has an important role in atherosclerosis. However, little is currently known regarding the effects of galectin‑3 on the oxLDL‑induced phenotypic transformation of vascular smooth muscle cells. In the present study, primary culture human umbilical vascular smooth muscle cells were treated with various oxLDL concentrations (0‑50 µg/ml) for 72 h, and phenotypic changes were subsequently recorded. The results of the present study suggested that oxLDL increases the expression levels of galectin‑3, and induces the phenotypic transformation of vascular smooth muscle cells. The oxLDL‑induced cells exhibited increased expression levels of osteopontin, a smooth muscle synthetic protein, and calponin and α‑actin, smooth muscle contractile proteins. The oxLDL‑induced changes in cellular phenotype were associated with increased migration, proliferation, and phagocytosis. Concordant with these results, oxLDL‑treated smooth muscle cells exhibited activation of canonical Wnt signaling, as determined by an increase in the protein expression levels of β‑catenin. Silencing of galectin‑3 by small interfering RNA reversed the phenotypic transformation and functional changes observed in the oxLDL‑treated cells, suggesting these changes were dependent on the activation of galectin‑3. In addition, galectin‑3 knockdown decreased the protein expression levels of β‑catenin in both the cytoplasm and nucleus; however, the mRNA expression levels of β‑catenin remained unchanged. These results suggest that galectin‑3 is responsible for the phenotypic transformation of human umbilical vascular smooth muscle cells, and the canonical Wnt/β-catenin signaling pathway may be involved in this process.

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1	Mill C and George SJ: Wnt signalling in smooth muscle cells and its role in cardiovascular disorders. Cardiovasc Res. 95:233–240. 2012. View Article : Google Scholar : PubMed/NCBI
2	Rensen SS, Doevendans PA and van Eys GJ: Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J. 15:100–108. 2007. View Article : Google Scholar : PubMed/NCBI
3	Dumic J, Dabelic S and Flögel M: Galectin-3: An open-ended story. Biochim Biophys Acta. 1760:616–635. 2006. View Article : Google Scholar : PubMed/NCBI
4	Markowska AI, Liu FT and Panjwani N: Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response. J Exp Med. 207:1981–1993. 2010. View Article : Google Scholar : PubMed/NCBI
5	Anand IS, Rector TS, Kuskowski M, Adourian A, Muntendam P and Cohn JN: Baseline and serial measurements of galectin-3 in patients with heart failure: Relationship to prognosis and effect of treatment with valsartan in the Val-HeFT. Eur J Heart Fail. 15:511–518. 2013. View Article : Google Scholar : PubMed/NCBI
6	Calvier L, Miana M, Reboul P, Cachofeiro V, Martinez-Martinez E, de Boer RA, Poirier F, Lacolley P, Zannad F, Rossignol P and López-Andrés N: Galectin-3 mediates aldosterone-induced vascular fibrosis. Arterioscler Thromb Vasc Biol. 33:67–75. 2013. View Article : Google Scholar
7	Morrow DA and O'Donoghue ML: Galectin-3 in cardiovascular disease: A possible window into early myocardial fibrosis. J Am Coll Cardiol. 60:1257–1258. 2012. View Article : Google Scholar : PubMed/NCBI
8	Wesley UV, Vemuganti R, Ayvaci ER and Dempsey RJ: Galectin-3 enhances angiogenic and migratory potential of microglial cells via modulation of integrin linked kinase signaling. Brain Res. 1496:1–9. 2013. View Article : Google Scholar
9	Arar C, Gaudin JC, Capron L and Legrand A: Galectin-3 gene (LGALS3) expression in experimental atherosclerosis and cultured smooth muscle cells. FEBS Lett. 430:307–311. 1998. View Article : Google Scholar : PubMed/NCBI
10	Massaeli H, Hurtado C, Austria JA and Pierce GN: Oxidized low-density lipoprotein induces cytoskeletal disorganization in smooth muscle cells. Am J Physiol. 277:H2017–H2025. 1999.PubMed/NCBI
11	Obradovic MM, Trpkovic A, Bajic V, Soskic S, Jovanovic A, Stanimirovic J, Panic M and Isenovic ER: Interrelatedness between C-reactive protein and oxidized low-density lipoprotein. Clin Chem Lab Med. 53:29–34. 2015. View Article : Google Scholar
12	Steinberg D: Oxidized low density lipoprotein - an extreme example of lipoprotein heterogeneity. Isr J Med Sci. 32:469–472. 1996.PubMed/NCBI
13	Auge N, Garcia V, Maupas-Schwalm F, Levade T, Salvayre R and Negre-Salvayre A: Oxidized LDL-induced smooth muscle cell proliferation involves the EGF receptor/PI-3 kinase/Akt and the sphingolipid signaling pathways. Arterioscler Thromb Vasc Biol. 22:1990–1995. 2002. View Article : Google Scholar : PubMed/NCBI
14	Leavesley DI, Schwartz MA, Rosenfeld M and Cheresh DA: Integrin beta 1- and beta 3-mediated endothelial cell migration is triggered through distinct signaling mechanisms. J Cell Biol. 121:163–170. 1993. View Article : Google Scholar : PubMed/NCBI
15	Argmann CA, Sawyez CG, Li S, Nong Z, Hegele RA, Pickering JG and Huff MW: Human smooth muscle cell subpopulations differentially accumulate cholesteryl ester when exposed to native and oxidized lipoproteins. Arterioscler Thromb Vasc Biol. 24:1290–1296. 2004. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
17	Karagiannis GS, Weile J, Bader GD and Minta J: Integrative pathway dissection of molecular mechanisms of moxLDL-induced vascular smooth muscle phenotype transformation. BMC Cardiovasc Disord. 13:42013. View Article : Google Scholar : PubMed/NCBI
18	Augé N, Maupas-Schwalm F, Elbaz M, Thiers JC, Waysbort A, Itohara S, Krell HW, Salvayre R and Nègre-Salvayre A: Role for matrix metalloproteinase-2 in oxidized low-density lipoprotein-induced activation of the sphingomyelin/ceramide pathway and smooth muscle cell proliferation. Circulation. 110:571–578. 2004. View Article : Google Scholar : PubMed/NCBI
19	Guyton JR, Lenz ML, Mathews B, Hughes H, Karsan D, Selinger E and Smith CV: Toxicity of oxidized low density lipoproteins for vascular smooth muscle cells and partial protection by antioxidants. Atherosclerosis. 118:237–249. 1995. View Article : Google Scholar : PubMed/NCBI
20	Deng DX, Spin JM, Tsalenko A, Vailaya A, Ben-Dor A, Yakhini Z, Tsao P, Bruhn L and Quertermous T: Molecular signatures determining coronary artery and saphenous vein smooth muscle cell phenotypes: Distinct responses to stimuli. Arterioscler Thromb Vasc Biol. 26:1058–1065. 2006. View Article : Google Scholar : PubMed/NCBI
21	Ding Z, Liu S, Yang B, Fan Y and Deng X: Effect of oxidized low-density lipoprotein concentration polarization on human smooth muscle cells' proliferation, cycle, apoptosis and oxidized low-density lipoprotein uptake. J R Soc Interface. 9:1233–1240. 2012. View Article : Google Scholar :
22	Shimura T, Takenaka Y, Tsutsumi S, Hogan V, Kikuchi A and Raz A: Galectin-3, a novel binding partner of beta-catenin. Cancer Res. 64:6363–6367. 2004. View Article : Google Scholar : PubMed/NCBI
23	Menini S, Iacobini C, Ricci C, Blasetti Fantauzzi C, Salvi L, Pesce CM, Relucenti M, Familiari G, Taurino M and Pugliese G: The galectin-3/RAGE dyad modulates vascular osteogenesis in atherosclerosis. Cardiovasc Res. 100:472–480. 2013. View Article : Google Scholar : PubMed/NCBI
24	Kim K, Mayer EP and Nachtigal M: Galectin-3 expression in macrophages is signaled by Ras/MAP kinase pathway and up-regulated by modified lipoproteins. Biochim Biophys Acta. 1641:13–23. 2003. View Article : Google Scholar : PubMed/NCBI
25	Liu J, Ren Y, Kang L and Zhang L: Oxidized low-density lipoprotein increases the proliferation and migration of human coronary artery smooth muscle cells through the upregulation of osteopontin. Int J Mol Med. 33:1341–1347. 2014.PubMed/NCBI
26	Dzau VJ, Braun-Dullaeus RC and Sedding DG: Vascular proliferation and atherosclerosis: New perspectives and therapeutic strategies. Nat Med. 8:1249–1256. 2002. View Article : Google Scholar : PubMed/NCBI
27	Nachtigal M, Ghaffar A and Mayer EP: Galectin-3 gene inactivation reduces atherosclerotic lesions and adventitial inflammation in ApoE-deficient mice. Am J Pathol. 172:247–255. 2008. View Article : Google Scholar :
28	Xue JH, Yuan Z, Wu Y, Liu Y, Zhao Y, Zhang WP, Tian YL, Liu WM, Liu Y and Kishimoto C: High glucose promotes intracellular lipid accumulation in vascular smooth muscle cells by impairing cholesterol influx and efflux balance. Cardiovasc Res. 86:141–150. 2010. View Article : Google Scholar
29	Rong JX, Shapiro M, Trogan E and Fisher EA: Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc Natl Acad Sci USA. 100:13531–13536. 2003. View Article : Google Scholar : PubMed/NCBI
30	Carthy JM, Luo Z and McManus BM: WNT3A induces a contractile and secretory phenotype in cultured vascular smooth muscle cells that is associated with increased gap junction communication. Lab Invest. 92:246–255. 2012. View Article : Google Scholar
31	Hao H, Gabbiani G and Bochaton-Piallat ML: Arterial smooth muscle cell heterogeneity: Implications for atherosclerosis and restenosis development. Arterioscler Thromb Vasc Biol. 23:1510–1520. 2003. View Article : Google Scholar : PubMed/NCBI
32	Rama A, Matsushita T, Charolidi N, Rothery S, Dupont E and Severs NJ: Up-regulation of connexin43 correlates with increased synthetic activity and enhanced contractile differentiation in TGF-β-treated human aortic smooth muscle cells. Eur J Cell Biol. 85:375–386. 2006. View Article : Google Scholar : PubMed/NCBI
33	Xie D, Yin D, Tong X, O'Kelly J, Mori A, Miller C, Black K, Gui D, Said JW and Koeffler HP: Cyr61 is overexpressed in gliomas and involved in integrin-linked kinase-mediated Akt and beta-catenin-TCF/Lef signaling pathways. Cancer Res. 64:1987–1996. 2004. View Article : Google Scholar : PubMed/NCBI
34	Lee KB, Ye S, Park MH, Park BH, Lee JS and Kim SM: p63-Mediated activation of the β-catenin/c-Myc signaling pathway stimulates esophageal squamous carcinoma cell invasion and metastasis. Cancer Lett. 353:124–132. 2014. View Article : Google Scholar : PubMed/NCBI
35	Kim SJ, Choi IJ, Cheong TC, Lee SJ, Lotan R, Park SH and Chun KH: Galectin-3 increases gastric cancer cell motility by up-regulating fascin-1 expression. Gastroenterology. 138:1035–1045. 2010. View Article : Google Scholar
36	Kobayashi T, Shimura T, Yajima T, Kubo N, Araki K, Tsutsumi S, Suzuki H, Kuwano H and Raz A: Transient gene silencing of galectin-3 suppresses pancreatic cancer cell migration and invasion through degradation of β-catenin. Int J Cancer. 129:2775–2786. 2011. View Article : Google Scholar : PubMed/NCBI
37	Zhang D, Chen ZG, Liu SH, Dong ZQ, Dalin M, Bao SS, Hu YW and Wei FC: Galectin-3 gene silencing inhibits migration and invasion of human tongue cancer cells in vitro via downregu-lating β-catenin. Acta Pharmacol Sin. 34:176–184. 2013. View Article : Google Scholar
38	Song S, Mazurek N, Liu C, Sun Y, Ding QQ, Liu K, Hung MC and Bresalier RS: Galectin-3 mediates nuclear beta-catenin accumulation and Wnt signaling in human colon cancer cells by regulation of glycogen synthase kinase-3beta activity. Cancer Res. 69:1343–1349. 2009. View Article : Google Scholar : PubMed/NCBI
39	Weir RA, Petrie CJ, Murphy CA, Clements S, Steedman T, Miller AM, McInnes IB, Squire IB, Ng LL, Dargie HJ and McMurray JJ: Galectin-3 and cardiac function in survivors of acute myocardial infarction. Circ Heart Fail. 6:492–498. 2013. View Article : Google Scholar : PubMed/NCBI