Resveratrol inhibits adventitial fibroblast proliferation and induces cell apoptosis through the SIRT1 pathway

Ling,Lin; Gu,Shaohua; Cheng,Yan

doi:10.3892/mmr.2016.6098

Resveratrol inhibits adventitial fibroblast proliferation and induces cell apoptosis through the SIRT1 pathway

Authors:
- Lin Ling
- Shaohua Gu
- Yan Cheng
View Affiliations

Affiliations: Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, Department of Nephrology, The Third People's Hospital of Kunshan, Kunshan, Jiangsu 215300, P.R. China, Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214000, P.R. China
Published online on: December 30, 2016 https://doi.org/10.3892/mmr.2016.6098
Pages: 567-572
Copyright: © Ling 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

Atherosclerosis is one of the most important causes of cardiovascular disease and studies have showed that adventitial fibroblasts, which are considered to be the most common cell type of the vascular adventitia, are involved in the development of early atherosclerotic plaques. Resveratrol is a plant polyphenolic compound confirmed to have anti‑atherosclerotic and cardioprotective effects. The aim of the present study was to investigate the effects of resveratrol on adventitial fibroblasts in vitro and to clarify the underlying mechanism. Adventitial fibroblasts were isolated from the thoracic aorta of 8‑week‑old SPF Sprague‑Dawley rats. Following pre‑treatment with different concentrations of resveratrol, cell viability, DNA synthesis ability, cell apoptosis and cell migration ability were assessed in vitro. Through transfection with small interfering (si)RNA targeting sirtuin 1 (SIRT1), the role of the SIRT1 pathway in these processes was evaluated. Western blot analysis was used to assess the protein expression of SIRT1. It was demonstrated that resveratrol inhibited the cell viability, DNA synthesis and migratory ability of the adventitial fibroblasts, and induced cell apoptosis in a concentration‑dependent manner in vitro. These effects were partly through the SIRT1 pathways. siRNA targeting SIRT1 successfully reversed the antiproliferative, antimigratory and pro‑apoptotic effects of resveratrol on adventitial fibroblasts. In conclusion, the data showed that resveratrol inhibited cell viability, DNA synthesis and cell migration, and induced cell apoptosis in the rat adventitial fibroblasts in vitro through the SIRT1 signaling pathway. As the activation and migration of adventitial fibroblasts contributes to the early development of atherosclerosis, this may be a mechanism underlying the anti‑atherosclerotic effect of resveratrol.

View Figures

View References

1	Koon CM, Woo KS, Leung PC and Fung KP: Salviae miltiorrhizae radix and puerariae lobatae radix herbal formula mediates anti-atherosclerosis by modulating key atherogenic events both in vascular smooth muscle cells and endothelial cells. J Ethnopharmacol. 138:175–183. 2011. View Article : Google Scholar : PubMed/NCBI
2	Tull SP, Anderson SI, Hughan SC, Watson SP, Nash GB and Rainger GE: Cellular pathology of atherosclerosis: Smooth muscle cells promote adhesion of platelets to cocultured endothelial cells. Circ Res. 98:98–104. 2006. View Article : Google Scholar : PubMed/NCBI
3	Wara AK, Mitsumata M, Yamane T, Kusumi Y and Yoshida Y: Gene expression in endothelial cells and intimal smooth muscle cells in atherosclerosis-prone or atherosclerosis-resistant regions of the human aorta. J Vasc Res. 45:303–313. 2008. View Article : Google Scholar : PubMed/NCBI
4	Haurani MJ and Pagano PJ: Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: Bellwether for vascular disease? Cardiovasc Res. 75:679–689. 2007. View Article : Google Scholar : PubMed/NCBI
5	Liu P, Zhang C, Feng JB, Zhao YX, Wang XP, Yang JM, Zhang MX, Wang XL and Zhang Y: Cross talk among Smad, MAPK, and integrin signaling pathways enhances adventitial fibroblast functions activated by transforming growth factor-beta1 and inhibited by Gax. Arterioscler Thromb Vasc Biol. 28:725–731. 2008. View Article : Google Scholar : PubMed/NCBI
6	Cai XJ, Chen L, Li L, Feng M, Li X, Zhang K, Rong YY, Hu XB, Zhang MX, Zhang Y and Zhang M: Adiponectin inhibits lipopolysaccharide-induced adventitial fibroblast migration and transition to myofibroblasts via AdipoR1-AMPK-iNOS pathway. Mol Endocrinol. 24:218–228. 2010. View Article : Google Scholar : PubMed/NCBI
7	Shen WL, Gao PJ, Che ZQ, Ji KD, Yin M, Yan C, Berk BC and Zhu DL: NAD(P)H oxidase-derived reactive oxygen species regulate angiotensin-II induced adventitial fibroblast phenotypic differentiation. Biochem Biophys Res Commun. 339:337–343. 2006. View Article : Google Scholar : PubMed/NCBI
8	Ruana BF, Lua XQ, Songa J and Zhu HL: Derivatives of Resveratrol: Potential agents in prevention and treatment of cardiovascular disease. Curr Med Chem. 19:4175–4183. 2012. View Article : Google Scholar : PubMed/NCBI
9	Tomé-Carneiro J, Gonzálvez M, Larrosa M, Garcia-Almagro FJ, Avilés-Plaza F, Parra S, Yáñez-Gascón MJ, Ruiz-Ros JA, García-Conesa MT, Tomás-Barberán FA and Espín JC: Consumption of a grape extract supplement containing resveratrol decreases oxidized LDL and ApoB in patients undergoing primary prevention of cardiovascular disease: A triple-blind, 6-month follow-up, placebo-controlled, randomized trial. Mol Nutr Food Res. 56:810–821. 2012. View Article : Google Scholar : PubMed/NCBI
10	Kim M, Chung H, Yoon C, Lee E, Kim T, Kwon M, Lee S, Rhee B and Park J: Increase of INS-1 cell apoptosis under glucose fluctuation and the involvement of FOXO-SIRT pathway. Diabetes Res Clin Pract. 98:132–139. 2012. View Article : Google Scholar : PubMed/NCBI
11	Peck B, Chen CY, Ho KK, Di Fruscia P, Myatt SS, Coombes RC, Fuchter MJ, Hsiao CD and Lam EW: SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther. 9:844–855. 2010. View Article : Google Scholar : PubMed/NCBI
12	Lai CS, Tsai ML, Badmaev V, Jimenez M, Ho CT and Pan MH: Xanthigen suppresses preadipocyte differentiation and adipogenesis through down-regulation of PPARγ and C/EBPs and modulation of SIRT-1, AMPK, and FoxO pathways. J Agric Food Chem. 60:1094–1101. 2012. View Article : Google Scholar : PubMed/NCBI
13	Shakibaei M, Buhrmann C and Mobasheri A: Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB ligand (RANKL) activation of NF-κB signaling and inhibit osteoclastogenesis in bone-derived cells. J Biol Chem. 286:11492–11505. 2011. View Article : Google Scholar : PubMed/NCBI
14	Simão F, Pagnussat AS, Seo JH, Navaratna D, Leung W, Lok J, Guo S, Waeber C, Salbego CG and Lo EH: Pro-angiogenic effects of resveratrol in brain endothelial cells: Nitric oxide-mediated regulation of vascular endothelial growth factor and metalloproteinases. J Cereb Blood Flow Metab. 32:884–895. 2012. View Article : Google Scholar : PubMed/NCBI
15	Li Y, Tao J, Zhang J, Tian X, Liu S, Sun M, Zhang X, Yan C and Han Y: Cellular repressor E1A-stimulated genes controls phenotypic switching of adventitial fibroblasts by blocking p38MAPK activation. Atherosclerosis. 225:304–314. 2012. View Article : Google Scholar : PubMed/NCBI
16	Liu Y, Liang C, Liu X, Liao B, Pan X, Ren Y, Fan M, Li M, He Z, Wu J and Wu Z: AGEs increased migration and inflammatory responses of adventitial fibroblasts via RAGE, MAPK and NF-κB pathways. Atherosclerosis. 208:34–42. 2010. View Article : Google Scholar : PubMed/NCBI
17	Heckenkamp J, Aleksic M, Gawenda M, Breuer S, Brabender J, Mahdavi A, Aydin F and Brunkwall JS: Modulation of human adventitial fibroblast function by photodynamic therapy of collagen matrix. Eur J Vasc Endovasc Surg. 28:651–659. 2004. View Article : Google Scholar : PubMed/NCBI
18	Schreiner CE, Kumerz M, Gesslbauer J, Schachner D, Joa H, Erker T, Atanasov AG, Heiss EH and Dirsch VM: Resveratrol blocks Akt activation in angiotensin II- or EGF-stimulated vascular smooth muscle cells in a redox-independent manner. Cardiovasc Res. 90:140–147. 2011. View Article : Google Scholar : PubMed/NCBI
19	Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, et al: SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15:675–690. 2012. View Article : Google Scholar : PubMed/NCBI
20	Busch F, Mobasheri A, Shayan P, Stahlmann R and Shakibaei M: Sirt-1 is required for the inhibition of apoptosis and inflammatory responses in human tenocytes. J Biol Chem. 287:25770–25781. 2012. View Article : Google Scholar : PubMed/NCBI
21	Singh N, Nigam M, Ranjan V, Sharma R, Balapure AK and Rath SK: Caspase mediated enhanced apoptotic action of cyclophosphamide- and resveratrol-treated MCF-7 cells. J Pharmacol Sci. 109:473–485. 2009. View Article : Google Scholar : PubMed/NCBI
22	Pozo-Guisado E, Merino JM, Mulero-Navarro S, Lorenzo-Benayas MJ, Centeno F, Alvarez-Barrientos A and Fernandez-Salguero PM: Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. Int J Cancer. 115:74–84. 2005. View Article : Google Scholar : PubMed/NCBI
23	Li L, Gao P, Zhang H, Chen H, Zheng W, Lv X, Xu T, Wei Y, Liu D and Liang C: SIRT1 inhibits angiotensin II-induced vascular smooth muscle cell hypertrophy. Acta Biochim Biophys Sin (Shanghai). 43:103–109. 2011. View Article : Google Scholar : PubMed/NCBI
24	Rahman M, Halade GV, Bhattacharya A and Fernandes G: The fat-1 transgene in mice increases antioxidant potential, reduces pro-inflammatory cytokine levels, and enhances PPAR-gamma and SIRT-1 expression on a calorie restricted diet. Oxid Med Cell Longev. 2:307–316. 2009. View Article : Google Scholar : PubMed/NCBI
25	Zhang W, Wang X and Chen T: Resveratrol induces mitochondria-mediated AIF and to a lesser extent caspase-9-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells. Mol Cell Biochem. 354:29–37. 2011. View Article : Google Scholar : PubMed/NCBI
26	Matos RS, Baroncini LA, Précoma LB, Winter G, Lambach PH, Caron EY, Kaiber F and Précoma DB: Resveratrol causes antiatherogenic effects in an animal model of atherosclerosis. Arq Bras Cardiol. 98:136–142. 2012.(In English, Portuguese). View Article : Google Scholar : PubMed/NCBI