Document Type : Original Article(s)


1 Assistant Professor, Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran

2 Associate Professor, Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

3 Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran


BACKGROUND: Matrix metalloproteinase 9 (MMP-9) is involved in extracellular matrix degradation and remodeling. An increase in MMP-9 expression by vascular component cells plays an important role in atherosclerotic plaque formation and rupture. Resveratrol, a polyphenolic substance, was suggested to play a role in preventing the progress of atherosclerotic disease. The aim of this study was to investigate the effect of resveratrol on MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) in vascular smooth muscle cells (VSMCs) after treatment with H2O2.METHODS: Cultured VSMCs were pre-treated with 0.2 mM of H2O2 before stimulation with different concentration of resveratrol. Expression of MMP-9, TIMP-1, and TIMP-3 genes were measured using real-time polymerase chain reaction (PCR) method, and MMP-9 protein level was detected using western blot analysis.RESULTS: Resveratrol at 120 μmol/l concentration reduced the elevated level of MMP-9 induced by H2O2 in VSMCs as 1.85 ± 0.35 folds (P < 0.05) and 8.70 ± 1.20 folds (P < 0.05) after 24 and 48 hours, respectively. Resveratrol increased the diminished level of TIMP-1 induced by H2O2 as 2.5 ± 0.48 folds following the treatment with 120 μmol/l after 48 hours (P < 0.05).CONCLUSION: Resveratrol as an antioxidant can decrease MMP-9 production, not only by suppressing MMP-9 expression, but also by augmenting TIMP-1 production. Altogether, resveratrol as an antioxidant can regulate the MMP-9/TIMP-1 balance, and may be considered as a preservative agent in the treatment and prevention of atherosclerosis.


  1. Hobeika MJ, Thompson RW, Muhs BE, Brooks PC, Gagne PJ. Matrix metalloproteinases in peripheral vascular disease. J Vasc Surg 2007; 45(4): 849-57.
  2. Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: Evolution, structure and function. Biochim Biophys Acta 2000; 1477(1-2): 267-83.
  3. Hung LM, Chen JK, Huang SS, Lee RS, Su MJ. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res 2000; 47(3): 549-55.
  4. Magyar K, Halmosi R, Palfi A, Feher G, Czopf L, Fulop A, et al. Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc 2012; 50(3): 179-87.
  5. Birrell MA, McCluskie K, Wong S, Donnelly LE, Barnes PJ, Belvisi MG. Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF-kappaB-independent mechanism. FASEB J 2005; 19(7): 840-1.
  6. Yu W, Fu YC, Zhou XH, Chen CJ, Wang X, Lin RB, et al. Effects of resveratrol on H(2)O(2)-induced apoptosis and expression of SIRTs in H9c2 cells. J Cell Biochem 2009; 107(4): 741-7.
  7. Gao D, Zhang X, Jiang X, Peng Y, Huang W, Cheng G, et al. Resveratrol reduces the elevated level of MMP-9 induced by cerebral ischemia-reperfusion in mice. Life Sci 2006; 78(22): 2564-70.
  8. Woo JH, Lim JH, Kim YH, Suh SI, Min DS, Chang JS, et al. Resveratrol inhibits phorbol myristate acetate-induced matrix metalloproteinase-9 expression by inhibiting JNK and PKC delta signal transduction. Oncogene 2004; 23(10): 1845-53.
  9. Byon CH, Javed A, Dai Q, Kappes JC, Clemens TL, Darley-Usmar VM, et al. Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. J Biol Chem 2008; 283(22): 15319-27.
  10. Chen Q, Jin M, Yang F, Zhu J, Xiao Q, Zhang L. Matrix metalloproteinases: Inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm 2013; 2013: 928315.
  11. Castro MM, Rizzi E, Rodrigues GJ, Ceron CS, Bendhack LM, Gerlach RF, et al. Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension. Free Radic Biol Med 2009; 46(9): 1298-307.
  12. Kaneko H, Anzai T, Morisawa M, Kohno T, Nagai T, Anzai A, et al. Resveratrol prevents the development of abdominal aortic aneurysm through attenuation of inflammation, oxidative stress, and neovascularization. Atherosclerosis 2011; 217(2): 350-7.
  13. Saneipour M, Ghatreh-Samani K, Heydarian E, Farrokhi E, Abdian N. Adiponectin inhibits oxidized low density lipoprotein-induced increase in matrix metalloproteinase 9 expression in vascular smooth muscle cells. ARYA Atheroscler 2015; 11(3): 191-5.
  14. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 1996; 98(11): 2572-9.
  15. Li YT, Shen F, Liu BH, Cheng GF. Resveratrol inhibits matrix metalloproteinase-9 transcription in U937 cells. Acta Pharmacol Sin 2003; 24(11): 1167-71.
  16. Scoditti E, Calabriso N, Massaro M, Pellegrino M, Storelli C, Martines G, et al. Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: A potentially protective mechanism in atherosclerotic vascular disease and cancer. Arch Biochem Biophys 2012; 527(2): 81-9.
  17. Meng L, Liu L, Zhou C, Pan S, Zhai X, Jiang C, et al. Polyphenols and polypeptides in chinese rice wine inhibit homocysteine-induced proliferation and migration of vascular smooth muscle cells. J Cardiovasc Pharmacol 2016; 67(6): 482-90.
  18. Setozaki S, Minakata K, Masumoto H, Hirao S, Yamazaki K, Kuwahara K, et al. Prevention of abdominal aortic aneurysm progression by oral administration of green tea polyphenol in a rat model. J Vasc Surg 2017; 65(6): 1803-12.
  19. Ma C, Wang Y, Dong L, Li M, Cai W. Anti-inflammatory effect of resveratrol through the suppression of NF-kappaB and JAK/STAT signaling pathways. Acta Biochim Biophys Sin (Shanghai) 2015; 47(3): 207-13.
  20. Woessner JF Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 1991; 5(8): 2145-54.
  21. Murphy G, Docherty AJ, Hembry RM, Reynolds JJ. Metalloproteinases and tissue damage. Br J Rheumatol 1991; 30(Suppl 1): 25-31.
  22. Sen T, Dutta A, Chatterjee A. Epigallocatechin-3-gallate (EGCG) downregulates gelatinase-B (MMP-9) by involvement of FAK/ERK/NFkappaB and AP-1 in the human breast cancer cell line MDA-MB-231. Anticancer Drugs 2010; 21(6): 632-44.
  23. Wei H, Wang S, Zhen L, Yang Q, Wu Z, Lei X, et al. Resveratrol attenuates the blood-brain barrier
  24. dysfunction by regulation of the MMP-9/TIMP-1 balance after cerebral ischemia reperfusion in rats. J Mol Neurosci 2015; 55(4): 872-9.
  25. Palmieri D, Aliakbarian B, Casazza AA, Ferrari N, Spinella G, Pane B, et al. Effects of polyphenol extract from olive pomace on anoxia-induced endothelial dysfunction. Microvasc Res 2012; 83(3): 281-9.
  26. Newby AC. Metalloproteinase production from macrophages-a perfect storm leading to atherosclerotic plaque rupture and myocardial infarction. Exp Physiol 2016; 101(11): 1327-37.
  27. Sang QX, Jin Y, Newcomer RG, Monroe SC, Fang X, Hurst DR, et al. Matrix metalloproteinase inhibitors as prospective agents for the prevention and treatment of cardiovascular and neoplastic diseases. Curr Top Med Chem 2006; 6(4): 289-316.