Gleditsia sinensis thorn extract inhibits the proliferation and migration of PDGF‑induced vascular smooth muscle cells

Park,Sung‑Soo; Kim,Wun‑Jae; Moon,Sung‑Kwon

doi:10.3892/mmr.2014.2422

Gleditsia sinensis thorn extract inhibits the proliferation and migration of PDGF‑induced vascular smooth muscle cells

Authors:
- Sung‑Soo Park
- Wun‑Jae Kim
- Sung‑Kwon Moon
View Affiliations

Affiliations: Department of Food Science and Nutrition, Jeju National University, Jeju, Jeju Special Self‑Governing Province 690‑756, Republic of Korea, Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk 361‑763, Republic of Korea, School of Food Science and Technology, Chung‑Ang University, Anseong, Gyeonggi‑Do 456‑756, Republic of Korea
Published online on: July 28, 2014 https://doi.org/10.3892/mmr.2014.2422
Pages: 2031-2038

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

The thorns of Gleditsia sinensis have been used to prevent or treat numerous diseases. The present study aimed to investigate the molecular mechanism of the ethanol extract of Gleditsia sinensis thorns (EEGS) on platelet‑derived growth factor (PDGF)‑treated vascular smooth muscle cells (VSMCs). EEGS treatment was found to inhibit DNA synthesis in PDG\F‑treated VSMCs in a dose‑dependent manner, without cell toxicity. These inhibitory effects were associated with G1‑phase cell‑cycle arrest, which was caused by the decreased expression of cyclins and cyclin‑dependent kinases (CDKs) and the upregulation of p27KIP1 expression in PDGF‑stimulated VSMCs. Among the pathways examined, EEGS treatment was observed to only inhibit the PDGF‑induced phosphorylation of Akt. In addition, EEGS treatment suppressed the migration and invasion of VSMCs in the presence of PDGF as determined by wound‑healing and Matrigel™ invasion assays. Furthermore, zymographic and western blot analyses revealed that EEGS treatment suppressed matrix metalloproteinase (MMP)‑9 expression in PDGF‑treated VSMCs, which was attributed to a reduction in the binding activities of nuclear factor κ-light-chain-enhancer of activated B cells (NF‑κB), activator protein (AP)‑1 and specificity protein (Sp)‑1. These results demonstrate that EEGS induces p27KIP1‑mediated G1‑phase cell‑cycle arrest, reduces Akt phosphorylation and prevents MMP‑9 expression by decreasing the binding activities of NF‑κB, AP‑1 and Sp‑1 in PDGF‑treated VSMCs, thus resulting in growth inhibition and the suppression of migration and invasion. These results may suggest a novel perspective for the use of EEGS in the treatment and prevention of vascular proliferative diseases.

View Figures

View References

1	Ross R: Cell biology of atherosclerosis. Annu Rev Physiol. 57:791–804. 1995. View Article : Google Scholar
2	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
3	Doran AC, Meller N and McNamara CA: Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscler Thromb Vasc Biol. 28:812–819. 2008. View Article : Google Scholar
4	Heldin CH and Westermark B: Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 79:1283–1316. 1999.PubMed/NCBI
5	Zhan Y, Kim S, Izumi Y, Izumiya Y, Nakao T, Miyazaki H and Iwao H: Role of JNK, p38, and ERK in platelet-derived growth factor-induced vascular proliferation, migration, and gene expression. Arterioscler Thromb Vasc Biol. 23:795–801. 2003. View Article : Google Scholar : PubMed/NCBI
6	Sherr CJ: G1 phase progression: cycling on cue. Cell. 79:551–555. 1994. View Article : Google Scholar : PubMed/NCBI
7	Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R and Beach D: p21 is a universal inhibitor of cyclin kinases. Nature. 366:701–704. 1993. View Article : Google Scholar : PubMed/NCBI
8	Toyoshima H and Hunter T: p27, a novel inhibitor of G1 cyclin-cdk protein kinase activity, is related to p21. Cell. 78:67–74. 1994. View Article : Google Scholar : PubMed/NCBI
9	Newby AC and Zaltsman AB: Molecular mechanisms in intimal hyperplasia. J Pathol. 190:300–309. 2000. View Article : Google Scholar : PubMed/NCBI
10	Cho A and Reidy MA: Matrix metalloproteinase-9 is necessary for the regulation of smooth muscle cell replication and migration after arterial injury. Circ Res. 91:845–851. 2002. View Article : Google Scholar : PubMed/NCBI
11	Galis ZS, Johnson C, Godin D, Magid R, Shipley JM, Senior RM and Ivan E: Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res. 91:852–859. 2002. View Article : Google Scholar : PubMed/NCBI
12	Cho A, Graves J and Reidy MA: Mitogen-activated protein kinases mediate matrix metalloproteinase-9 expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 20:2527–2532. 2000. View Article : Google Scholar : PubMed/NCBI
13	Moon SK, Cha BY and Kim CH: ERK1/2 mediates TNF-alpha-induced matrix metalloproteinase-9 expression in human vascular smooth muscle cells via the regulation of NF-kappaB and AP-1: Involvement of the ras dependent pathway. J Cell Physiol. 198:417–427. 2004. View Article : Google Scholar
14	Dollery CM, McEwan JR and Henney AM: Matrix metalloproteinases and cardiovascular disease. Circ Res. 77:863–868. 1995. View Article : Google Scholar : PubMed/NCBI
15	Hansson GK and Robertson AK: TGF-beta in atherosclerosis. Arterioscler Thromb Vasc Biol. 24:E1372004. View Article : Google Scholar : PubMed/NCBI
16	Lim JC, Park JH, Budesinsky M, Kasal A, Han YH, Koo BS, Lee SI and Lee DU: Antimutagenic constituents from the thorns of Gleditsia sinensis. Chem Pharm Bull (Tokyo). 53:561–564. 2005. View Article : Google Scholar : PubMed/NCBI
17	Zhou L, Li D, Wang J, Liu Y and Wu J: Antibacterial phenolic compounds from the spines of Gleditsia sinensis Lam. Nat Prod Res. 21:283–291. 2007. View Article : Google Scholar : PubMed/NCBI
18	Li WH, Zhang XM, Tian RR, Zheng YT, Zhao WM and Qiu MH: A new anti-HIV lupane acid from Gleditsia sinensis Lam. J Asian Nat Prod Res. 9:551–555. 2007. View Article : Google Scholar : PubMed/NCBI
19	Shin TY and Kim DK: Inhibitory effect of mast cell-dependent anaphylaxis by Gleditsia sinensis. Arch Pharm Res. 23:401–406. 2000. View Article : Google Scholar : PubMed/NCBI
20	Park E and Shin MJ: Anti-inflammatory activity of aqueous extract from Gleditsiae Spina. J Pharmaceut Soc Korea. 37:124–128. 1993.
21	Lee SJ, Cho YH, Kim H, Park K, Park SK, Ha SD, Kim WJ and Moon SK: Inhibitory effects of the ethanol extract of Gleditsia sinensis thorns on human colon cancer HCT116 cells in vitro and in vivo. Oncol Rep. 22:1505–1512. 2009.PubMed/NCBI
22	Zhou L, Li D, Jiang W, Qin Z, Zhao S, Qiu M and Wu J: Two ellagic acid glycosides from Gleditsia sinensis Lam. with antifungal activity on Magnaporthe grisea. Nat Prod Res. 21:303–309. 2007.
23	Lee SJ, Park SS, Kim WJ and Moon SK: Gleditsia sinensis thorn extract inhibits proliferation and TNF-α-induced MMP-9 expression in vascular smooth muscle cells. Am J Chin Med. 40:373–386. 2012. View Article : Google Scholar
24	Tanner FC, Yang ZY, Duckers E, Gordon D, Nabel GJ and Nabel EG: Expression of cyclin-dependent kinase inhibitors in vascular disease. Circ Res. 82:396–403. 1998. View Article : Google Scholar : PubMed/NCBI
25	Chen D, Krasinski K, Sylvester A, Chen J, Nisen PD and Andrés V: Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27(KIP1), an inhibitor of neointima formation in the rat carotid artery. J Clin Invest. 99:2334–2341. 1997. View Article : Google Scholar : PubMed/NCBI
26	Moon SK, Kim HM, Lee YC and Kim CH: Disialoganglioside (GD3) synthase gene expression suppresses vascular smooth muscle cell responses via the inhibition of ERK1/2 phosphorylation, cell cycle progression, and matrix metalloproteinase-9 expression. J Biol Chem. 279:33063–33070. 2004. View Article : Google Scholar : PubMed/NCBI
27	Shankland SJ and Wolf G: Cell cycle regulatory proteins in renal disease: role in hypertrophy, proliferation, and apoptosis. Am J Physiol Renal Physiol. 278:F515–F529. 2000.PubMed/NCBI
28	Uchida K, Sasahara M, Morigami N, Hazama F and Kinoshita M: Expression of platelet-derived growth factor B-chain in neointimal smooth muscle cells of balloon injured rabbit femoral arteries. Atherosclerosis. 124:9–23. 1996. View Article : Google Scholar : PubMed/NCBI