Oleic acid induces A7r5 cell proliferation and migration associated with increased expression of HGF and p‑p38

Li,Jingjing; Chu,Ting; Yang,Maosheng

doi:10.3892/mmr.2021.12123

Oleic acid induces A7r5 cell proliferation and migration associated with increased expression of HGF and p‑p38

Authors:
- Jingjing Li
- Ting Chu
- Maosheng Yang
View Affiliations

Affiliations: Department of Clinical Medicine, Jishou University School of Medicine, Jishou, Hunan 416000, P.R. China, Department of Nursing, Jishou University School of Medicine, Jishou, Hunan 416000, P.R. China, Laboratory of Disorders Genes and Department of Pharmacology, Jishou University School of Pharmacy, Jishou, Hunan 416000, P.R. China
Published online on: April 27, 2021 https://doi.org/10.3892/mmr.2021.12123
Article Number: 484
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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 phenotypes and mechanisms underlying the proliferation and migration of vascular smooth muscle cells (VSMCs) induced by oleic acid (OA) are not completely understood. Therefore, the aim of the present study was to further elucidate the effects of OA on the proliferation and migration of VSMCs. Using A7r5 cells, the hepatocyte growth factor (HGF) inhibitor PHA665752 and the p38 MAPK inhibitor SB203580 were utilized, and Cell Counting Kit‑8 (CCK‑8) assays, Transwell assays, flow cytometry, ELISAs, western blotting and reverse transcription‑quantitative PCR (RT‑qPCR) were conducted to assess the effects of OA. CCK‑8 assays indicated that OA promoted (at 5 and 50 µmol/l) or inhibited (at 800 µmol/l) A7r5 cell proliferation in a time‑ and concentration‑dependent manner (P<0.05). Transwell assays revealed that OA also promoted (at 50 µmol/l) or inhibited (at 800 µmol/l) A7r5 cell migration (P<0.05). Moreover, cell‑cycle analysis identified that 50 µmol/l OA reduced the cellular population in the G₀/G₁ phase and enhanced the cellular population in the S phase (P<0.05), whereas 800 µmol/l OA increased the cell number in the G₀/G₁ phase and decreased the cell number in the S phase (P<0.05). In addition, OA promoted (at 50 µmol/l) or inhibited (at 800 µmol/l) the expression level of HGF in A7r5 cells, as demonstrated via ELISA, western blotting and RT‑qPCR analyses (P<0.05). It was also found that OA promoted (at 50 µmol/l) or inhibited (at 800 µmol/l) the expression level of phosphorylated (p)‑p38 in A7r5 cells, as indicated by western blotting (P<0.05). Furthermore, the cell proliferation, migration and HGF expression induced by OA (50 µmol/l) were mitigated by treatment with PHA665752 (0.1 µmol/l) (P<0.05), and the cell proliferation, migration and p‑p38 expression induced by OA (50 µmol/l) were mitigated by SB203580 (2 µmol/l) (P<0.05). Thus, the results suggested that OA served a role in the proliferation and migration of VSMCs via HGF and the p38 MAPK pathway. Moreover, the proliferation and migration of VSMCs induced by OA was associated with increased expression levels of HGF and p‑p38. Taken together, OA, HGF and p38 MAPK may be potential therapeutic targets for the treatment of atherosclerosis.

View Figures

View References

1	Zhao WH, Zhang J, You Y, Man QQ, Li H, Wang CR, Zhai Y, Li Y, Jin SG and Yang XG: Epidemiologic characteristics of dyslipidemia in people aged 18 years and over in China. Zhonghua Yu Fang Yi Xue Za Zhi. 39:306–310. 2005.(In Chinese). PubMed/NCBI
2	Després JP and Lemieux I: Abdominal obesity and metabolic syndrome. Nature. 444:881–887. 2006. View Article : Google Scholar
3	Xie C, Wang ZC, Liu XF and Yang MS: The common biological basis for common complex diseases: Evidence from lipoprotein lipase gene. Eur J Hum Genet. 18:3–7. 2010. View Article : Google Scholar : PubMed/NCBI
4	Hardy S, Langelier Y and Prentki M: Oleate activates phosphatidylinositol 3-kinase and promotes proliferation and reduces apoptosis of MDA-MB-231 breast cancer cells, whereas palmitate has opposite effects. Cancer Res. 60:6353–6358. 2000.PubMed/NCBI
5	Sargsyan E, Artemenko K, Manukyan L, Bergquist J and Bergsten P: Oleate protects beta-cells from the toxic effect of palmitate by activating pro-survival pathways of the ER stress response. Biochim Biophys Acta. 1861:1151–1160. 2016. View Article : Google Scholar : PubMed/NCBI
6	Ross R: The pathogenesis of atherosclerosis - an updata. N Engl J Med. 314:488–500. 1986. View Article : Google Scholar : PubMed/NCBI
7	Basatemur GL, Jørgensen HF, Clarke MCH, Bennett MR and Mallat Z: Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol. 16:727–744. 2019. View Article : Google Scholar : PubMed/NCBI
8	Bennett MR, Sinha S and Owens GK: Vascular smooth muscle cells in atherosclerosis. Circ Res. 118:692–702. 2016. View Article : Google Scholar : PubMed/NCBI
9	Zhou XX, Zhou XH, Yang HM and Su PQ: High triglyceride serum promotes the proliferation of vascular smooth muscle cells. Chin J Cardiol. 28:3162000.(In Chinese). doi:10.3760/j:issn:0253-3758.2000.04.024.
10	Yin Z, Gao HK, Li LS, Luan RH and Wang HC: Effects of atorvastatin on hyperlipemic serum induced proliferation of vascular smooth muscle cells in rats. Chin Hear J. 20:180–183. 2008.(In Chinese).
11	Mattern HM and Hardin CD: Vascular metabolic dysfunction and lipotoxicity. Physiol Res. 56:149–158. 2007.PubMed/NCBI
12	Wang YQ and Yang MS: Effects of glyceryl trioleate on the proliferation of rat aortic smooth muscle cells. J Chongqing Med Univ. 39:1384–1390. 2014.(In Chinese).
13	Yang MS and Wang YQ: Bidirectional effects of medium chain triglyceride on the proliferation of vascular smooth muscle cells. Chin J Arterioscler. 24:551–556. 2016.(In Chinese). doi: 10.13406/jcnki.cyxb.001052. PubMed/NCBI
14	Liotti A, Cosimato V, Mirra P, Calì G, Conza D, Secondo A, Luongo G, Terracciano D, Formisano P, Beguinot F, et al: Oleic acid promotes prostate cancer malignant phenotype via the G protein-coupled receptor FFA1/GPR40. J Cell Physiol. 233:7367–7378. 2018. View Article : Google Scholar : PubMed/NCBI
15	Yang C, Lim W, Bazer FW and Song G: Oleic acid stimulation of motility of human extravillous trophoblast cells is mediated by stearoyl-CoA desaturase-1 activity. Mol Hum Reprod. 23:755–770. 2017. View Article : Google Scholar : PubMed/NCBI
16	Nakamura T, Sakai K, Nakamura T and Matsumoto K: Hepatocyte growth factor twenty years on: Much more than a growth factor. J Gastroenterol Hepatol. 26 (Suppl 1):S188–S202. 2011. View Article : Google Scholar
17	Forte G, Minieri M, Cossa P, Antenucci D, Sala M, Gnocchi V, Fiaccavento R, Carotenuto F, De Vito P, Baldini PM, et al: Hepatocyte growth factor effects on mesenchymal stem cells: Proliferation, migration, and differentiation. Stem Cells. 24:23–33. 2006. View Article : Google Scholar : PubMed/NCBI
18	Greene EL, Lu G, Zhang D and Egan BM: Signaling events mediating the additive effects of oleic acid and angiotensin II on vascular smooth muscle cell migration. Hypertension. 37:308–312. 2001. View Article : Google Scholar : PubMed/NCBI
19	Wan Q, Liu Z and Yang Y: Puerarin inhibits vascular smooth muscle cells proliferation induced by fine particulate matter via suppressing of the p38 MAPK signaling pathway. BMC Complement Altern Med. 18:1462018. View Article : Google Scholar : PubMed/NCBI
20	Kyriakis JM and Avruch J: Mammalian MAPK signal transduction pathways activated by stress and inflammation: A 10-year update. Physiol Rev. 92:689–737. 2012. View Article : Google Scholar : PubMed/NCBI
21	Cuenda A and Rousseau S: p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 1773:1358–1375. 2007. View Article : Google Scholar : PubMed/NCBI
22	Karin M and Gallagher E: From JNK to pay dirt: Jun kinases, their biochemistry, physiology and clinical importance. IUBMB Life. 57:283–295. 2005. View Article : Google Scholar : PubMed/NCBI
23	Jacob T, Ascher E, Alapat D, Olevskaia Y and Hingorani A: Activation of p38MAPK signaling cascade in a VSMC injury model: Role of p38MAPK inhibitors in limiting VSMC proliferation. Eur J Vasc Endovasc Surg. 29:470–478. 2005. View Article : Google Scholar : PubMed/NCBI
24	Awasthi V and King RJ: PKC, p42/p44 MAPK, and p38 MAPK are required for HGF-induced proliferation of H441 cells. Am J Physiol Lung Cell Mol Physiol. 279:L942–L949. 2000. View Article : Google Scholar : PubMed/NCBI
25	Chattopadhyay N, Tfelt-Hansen J and Brown EM: PKC, p42/44 MAPK and p38 MAPK regulate hepatocyte growth factor secretion from human astrocytoma cells. Brain Res Mol Brain Res. 102:73–82. 2002. View Article : Google Scholar : PubMed/NCBI
26	Yao J, Ke J, Zhou Z, Tan G, Yin Y, Liu M, Chen J and Wu W: Combination of HGF and IGF-1 promotes connexin 43 expression and improves ventricular arrhythmia after myocardial infarction through activating the MAPK/ERK and MAPK/p38 signaling pathways in a rat model. Cardiovasc Diagn Ther. 9:346–354. 2019. View Article : Google Scholar : PubMed/NCBI
27	Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, et al: A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 63:7345–7355. 2003.PubMed/NCBI
28	Yun MR, Lee JY, Park HS, Heo HJ, Park JY, Bae SS, Hong KW, Sung SM and Kim CD: Oleic acid enhances vascular smooth muscle cell proliferation via phosphatidylinositol 3-kinase/Akt signaling pathway. Pharmacol Res. 54:97–102. 2006. View Article : Google Scholar : PubMed/NCBI
29	Qi W, Ding D and Salvi RJ: Cytotoxic effects of dimethyl sulphoxide (DMSO) on cochlear organotypic cultures. Hear Res. 236:52–60. 2008. View Article : Google Scholar : PubMed/NCBI
30	Xiang Q, Zhen Z, Deng DY, Wang J and Chen Y, Li J, Zhang Y, Wang F, Chen N, Chen H and Chen Y: Tivantinib induces G2/M arrest and apoptosis by disrupting tubulin polymerization in hepatocellular carcinoma. J Exp Clin Cancer Res. 34:1182015. View Article : Google Scholar : PubMed/NCBI
31	Sreekanth GP, Chuncharunee A, Sirimontaporn A, Panaampon J, Noisakran S, Yenchitsomanus PT and Limjindaporn T: SB203580 modulates p38 MAPK signaling and dengue virus-induced liver injury by reducing MAPKAPK2, HSP27, and ATF2 phosphorylation. PLoS One. 11:e01494862016. View Article : Google Scholar : PubMed/NCBI
32	He T, Liu S, Chen S, Ye J, Wu X, Bian Z and Chen X: The p38 MAPK inhibitor SB203580 abrogates tumor necrosis factor-induced proliferative expansion of mouse CD4⁺Foxp3⁺ regulatory T cells. Front Immunol. 9:15562018. View Article : Google Scholar : PubMed/NCBI
33	Liu T, Li Q, Sun Q, Zhang Y, Yang H, Wang R, Chen L and Wang W: MET inhibitor PHA-665752 suppresses the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells. Biochem Biophys Res Commun. 449:49–54. 2014. View Article : Google Scholar : PubMed/NCBI
34	Xiang QF, Zhan MX, Li Y, Liang H, Hu C, Huang YM, Xiao J, He X, Xin YJ, Chen MS and Lu LG: Activation of MET promotes resistance to sorafenib in hepatocellular carcinoma cells via the AKT/ERK1/2-EGR1 pathway. Artif Cells Nanomed Biotechnol. 47:83–89. 2019. View Article : Google Scholar : PubMed/NCBI
35	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 : PubMed/NCBI
36	Bielinski SJ, Berardi C, Decker PA, Larson NB, Bell EJ, Pankow JS, Sale MM, Tang W, Hanson NQ, Wassel CL, et al: Hepatocyte growth factor demonstrates racial heterogeneity as a biomarker for coronary heart disease. Heart. 103:1185–1193. 2017. View Article : Google Scholar : PubMed/NCBI
37	Bell EJ, Larson NB, Decker PA, Pankow JS, Tsai MY, Hanson NQ, Wassel CL, Longstreth WT Jr and Bielinski SJ: Hepatocyte growth factor is positively associated with risk of stroke: The MESA (multi-ethnic study of atherosclerosis). Stroke. 47:2689–2694. 2016. View Article : Google Scholar : PubMed/NCBI
38	Gallo S, Sala V, Gatti S and Crepaldi T: Cellular and molecular mechanisms of HGF/Met in the cardiovascular system. Clin Sci (Lond). 129:1173–1193. 2015. View Article : Google Scholar : PubMed/NCBI
39	Bell EJ, Decker PA, Tsai MY, Pankow JS, Hanson NQ, Wassel CL, Larson NB, Cohoon KP, Budoff MJ, Polak JF, et al: Hepatocyte growth factor is associated with progression of atherosclerosis: The multi-ethnic study of atherosclerosis (MESA). Atherosclerosis. 272:162–167. 2018. View Article : Google Scholar : PubMed/NCBI
40	Nakamura T and Mizuno S: The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc Jpn Acad Ser B Phys Biol Sci. 86:588–610. 2010. View Article : Google Scholar : PubMed/NCBI
41	Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, Kim WJ, Okimoto RA, Bell DW, Sgroi DC, et al: Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci USA. 103:2316–2321. 2006. View Article : Google Scholar : PubMed/NCBI
42	Mukohara T, Civiello G, Davis IJ, Taffaro ML, Christensen J, Fisher DE, Johnson BE and Jänne PA: Inhibition of the met receptor in mesothelioma. Clin Cancer Res. 11:8122–8130. 2005. View Article : Google Scholar : PubMed/NCBI
43	Lu G, Meier KE, Jaffa AA, Rosenzweig SA and Egan BM: Oleic acid and angiotensin II induce a synergistic mitogenic response in vascular smooth muscle cells. Hypertension. 31:978–985. 1998. View Article : Google Scholar : PubMed/NCBI
44	Lu G, Greene EL, Nagai T and Egan BM: Reactive oxygen species are critical in the oleic acid-mediated mitogenic signaling pathway in vascular smooth muscle cells. Hypertension. 32:1003–1010. 1998. View Article : Google Scholar : PubMed/NCBI
45	Ahn HJ, Park J, Song JS, Ju MK, Kim MS, Ha H, Song KH and Kim YS: Mycophenolic acid inhibits oleic acid-induced vascular smooth muscle cell activation by inhibiting cellular reactive oxygen species. Transplantation. 84:634–638. 2007. View Article : Google Scholar : PubMed/NCBI
46	Ou TT, Lin MC, Wu CH, Lin WL and Wang CJ: Gallic acid attenuates oleic acid-induced proliferation of vascular smooth muscle cell through regulation of AMPK-eNOS-FAS signaling. Curr Med Chem. 20:3944–3953. 2013. View Article : Google Scholar : PubMed/NCBI
47	Lin MC, Ou TT, Chang CH, Chan KC and Wang CJ: Protocatechuic acid inhibits oleic acid-induced vascular smooth muscle cell proliferation through activation of AMP-activated protein kinase and cell cycle arrest in G0/G1 phase. J Agric Food Chem. 63:235–241. 2015. View Article : Google Scholar : PubMed/NCBI
48	Zhu Y, Schwarz S, Ahlemeyer B, Grzeschik S, Klumpp S and Krieglstein J: Oleic acid causes apoptosis and dephosphorylates Bad. Neurochem Int. 46:127–135. 2005. View Article : Google Scholar : PubMed/NCBI
49	Carrillo C, Cavia Mdel M and Alonso-Torre SR: Antitumor effect of oleic acid; mechanisms of action: A review. Nutr Hosp. 27:1860–1865. 2012.PubMed/NCBI
50	Cheng CI, Lee YH, Chen PH, Lin YC, Chou MH and Kao YH: Free fatty acids induce autophagy and LOX-1 upregulation in cultured aortic vascular smooth muscle cells. J Cell Biochem. 118:1249–1261. 2017. View Article : Google Scholar : PubMed/NCBI
51	Artwohl M, Lindenmair A, Roden M, Waldhäusl WK, Freudenthaler A, Klosner G, Ilhan A, Luger A and Baumgartner-Parzer SM: Fatty acids induce apoptosis in human smooth muscle cells depending on chain length, saturation, and duration of exposure. Atherosclerosis. 202:351–362. 2009. View Article : Google Scholar : PubMed/NCBI
52	Zhang C, Wang W, Lin J, Xiao J and Tian Y: lncRNA CCAT1 promotes bladder cancer cell proliferation, migration and invasion. Int Braz J Urol. 45:549–559. 2019. View Article : Google Scholar : PubMed/NCBI
53	Belal SA, Sivakumar AS, Kang DR, Cho S, Choe HS and Shim KS: Modulatory effect of linoleic and oleic acid on cell proliferation and lipid metabolism gene expressions in primary bovine satellite cells. Anim Cells Syst (Seoul). 22:324–333. 2018. View Article : Google Scholar : PubMed/NCBI