Document Type : Original Article(s)

Authors

1 Associate Professor, Department of Clinical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Assistant Professor, Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Associate Professor, Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Associate Professor, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

5 Assistant Professor, Psychiatry and Behavioral Sciences Research Center AND Department of Psychiatry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

6 Associate Professor, Pharmacological Research Center of Medicinal Plants AND Department of Clinical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

BACKGROUND: Coronary artery disease (CAD) is the most common type of cardiovascular disease. Increasing the expression and activity of matrix metalloproteinases (MMPs) facilitates vascular remodeling and cardiovascular complications. Curcumin (the active ingredient of turmeric) is a potent natural anti-inflammatory agent, with cardiovascular protective effects. The present study was a clinical trial for investigating the effects of curcumin on activity and gene expression of MMP-2 and MMP-9 in patients with CAD.METHODS: In this study, 70 patients with CAD (with 40%-50% stenosis) were randomly divided into two groups of curcumin (80 mg nanomicelle per day) and placebo. The intervention lasted 3 months. The activity levels of MMP-2 and MMP-9 in serum samples of patients were measured using gelatin zymography assay before and after the intervention. MMP-2 and MMP-9 gene expression in peripheral blood mononuclear cells (PBMCs) was also analyzed using real-time polymerase chain reaction (PCR). Statistical significance was set at P < 0.0500.RESULTS: After 3 months of medication, the expression of MMP-9 produced by PBMCs significantly decreased in the curcumin group (0.811 ± 0.25) in comparison with the placebo group (2.23 ± 0.94) (P < 0.0001). Furthermore, the zymographic analysis showed that the administration of curcumin significantly inhibited the activity levels of MMP-2 (12469.7 ± 5308.64 pixels) and MMP-9 (14007.2 ± 5371.67 pixels) in comparison with that in patients receiving placebo (MMP-2: 17613.8 ± 5250.68 pixels; MMP-9: 20010.1 ± 3259.37 pixels) (P < 0.0500).CONCLUSION: Our results show that curcumin can significantly reduce the expression and activity of MMP-2 and MMP-9. Because of the anti-inflammatory effects of curcumin, this compound can be considered as a new strategy for the prevention of cardiovascular events.

Keywords

  1. Sanderson JE, Mayosi B, Yusuf S, Reddy S, Hu S, Chen Z, et al. Global burden of cardiovascular disease. Heart 2007; 93(10): 1175.
  2. Haarala A. Inflammation and early atherosclerosis [Thesis]; Tampere, Finland: University of Tampere; 2012.
  3. Katrib A, Tak PP, Bertouch JV, Cuello C, McNeil HP, Smeets TJ, et al. Expression of chemokines and matrix metalloproteinases in early rheumatoid arthritis. Rheumatology (Oxford) 2001; 40(9): 988-94.
  4. Huang J. Role of matrix metalloproteinase-2 in therosclerosis and abdominal aortic aneurysms in apolipoprotein e deficient mice [Thesis]; Lexington, KY: University of Kentucky; 2005.
  5. Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res 1994; 75(3): 539-45.
  6. Momi S, Falcinelli E, Giannini S, Ruggeri L, Cecchetti L, Corazzi T, et al. Loss of matrix metalloproteinase 2 in platelets reduces arterial thrombosis in vivo. J Exp Med 2009; 206(11): 2365-79.
  7. Kapakos G, Youreva V, Srivastava AK. Cardiovascular protection by curcumin: Molecular aspects. Indian J Biochem Biophys 2012; 49(5):
  8. -15.
  9. Rahimi H, Jaafari M, Mohammadpour A, Abnous K, Ghayour Mobarhan M, Ramezanzadeh E, et al. Curcumin: Reintroduced Therapeutic Agent from Traditional Medicine for Alcoholic Liver Disease. Asia Pac J Med Toxicol 2015; 4(1): 25-30.
  10. Rahimi HR, Nedaeinia R, Sepehri SA, Nikdoust S, Kazemi OR. Novel delivery system for natural products: Nano-curcumin formulations. Avicenna J Phytomed 2016; 6(4): 383-98.
  11. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: Problems and promises. Mol Pharm 2007; 4(6):
  12. -18.
  13. Hatamipour M, Sahebkar A, Alavizadeh SH, Dorri M, Jaafari MR. Novel nanomicelle formulation to enhance bioavailability and stability of curcuminoids. Iran J Basic Med Sci 2019; 22(3): 282-9.
  14. Kosalova D, Bezakova L, Raekovac L, Mosovska S, Sturdik E. Therapeutic potential of curcumin in medicinal chemistry. Acta Chimica Slovaca 2013; 6(1): 89-99.
  15. Wongcharoen W, Phrommintikul A. The protective role of curcumin in cardiovascular diseases. Int J Cardiol 2009; 133(2): 145-51.
  16. Singh S, Aggarwal BB. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 1995; 270(42): 24995-5000.
  17. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: From ancient medicine to current clinical trials. Cell Mol Life Sci 2008; 65(11): 1631-52.
  18. Chuengsamarn S, Rattanamongkolgul S, Phonrat B, Tungtrongchitr R, Jirawatnotai S. Reduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: A randomized controlled trial. J Nutr Biochem 2014; 25(2): 144-50.
  19. Ghorbani Z, Hekmatdoost A, Mirmiran P. Anti-hyperglycemic and insulin sensitizer effects of turmeric and its principle constituent curcumin. Int J Endocrinol Metab 2014; 12(4): e18081.
  20. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: A randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9(2): 194-205.
  21. Rahimi HR, Mohammadpour AH, Dastani M, Jaafari MR, Abnous K, Ghayour Mobarhan M, et al. The effect of nano-curcumin on HbA1c, fasting blood glucose, and lipid profile in diabetic subjects: A randomized clinical trial. Avicenna J Phytomed 2016; 6(5): 567-77.
  22. Toth M, Fridman R. Assessment of Gelatinases (MMP-2 and MMP-9) by Gelatin Zymography. Methods Mol Med 2001; 57: 163-74.
  23. Libby P, Aikawa M. Mechanisms of plaque stabilization with statins. Am J Cardiol 2003; 91(4A): 4B-8B.
  24. Dupuis J. Mechanisms of acute coronary syndromes and the potential role of statins. Atheroscler Suppl 2001; 2(1): 9-14.
  25. Simionescu M, Sima A. Morphology of atherosclerotic lesions. In: Wick G, Grundtman C, Editors. Inflammation and atherosclerosis. Berlin, Germany: Springer Science & Business Media; 2011. p. 19-37.
  26. Jones CB, Sane DC, Herrington DM. Matrix metalloproteinases: A review of their structure and role in acute coronary syndrome. Cardiovasc Res 2003; 59(4): 812-23.
  27. Shishodia S, Sethi G, Aggarwal BB. Curcumin: Getting back to the roots. Ann N Y Acad Sci 2005; 1056: 206-17.
  28. Saja K, Babu MS, Karunagaran D, Sudhakaran PR. Anti-inflammatory effect of curcumin involves downregulation of MMP-9 in blood mononuclear cells. Int Immunopharmacol 2007; 7(13): 1659-67.
  29. Kohli S, Chhabra A, Jaiswal A, Rustagi Y, Sharma M, Rani V. Curcumin suppresses gelatinase B mediated norepinephrine induced stress in H9c2 cardiomyocytes. PLoS One 2013; 8(10): e76519.
  30. Kim JH, Shim JS, Lee SK, Kim KW, Rha SY, Chung HC, et al. Microarray-based analysis of anti-angiogenic activity of demethoxycurcumin on human umbilical vein endothelial cells: Crucial involvement of the down-regulation of matrix metalloproteinase. Jpn J Cancer Res 2002; 93(12): 1378-85.
  31. Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets 2011; 12(3): 332-47.
  32. Bond M, Chase AJ, Baker AH, Newby AC. Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells. Cardiovasc Res 2001; 50(3): 556-65.
  33. Divya CS, Pillai MR. Antitumor action of curcumin in human papillomavirus associated cells involves downregulation of viral oncogenes, prevention of NFkB and AP-1 translocation, and modulation of apoptosis. Mol Carcinog 2006; 45(5): 320-32.
  34. Vincenti MP. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol 2001; 151: 121-48.
  35. Parodi FE, Mao D, Ennis TL, Pagano MB, Thompson RW. Oral administration of diferuloylmethane (curcumin) suppresses proinflammatory cytokines and destructive connective tissue remodeling in experimental abdominal aortic aneurysms. Ann Vasc Surg 2006; 20(3): 360-8.
  36. Aoyagi M, Yamamoto M, Azuma H, Nagashima G, Niimi Y, Tamaki M, et al. Immunolocalization of matrix metalloproteinases in rabbit carotid arteries after balloon denudation. Histochem Cell Biol 1998; 109(2): 97-102.
  37. Newby AC, Zaltsman AB. Fibrous cap formation or destruction-the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovasc Res 1999; 41(2): 345-60.
  38. Zhong Y, Yu W, Feng J, Fan Z, Li J. Curcumin suppresses tumor necrosis factor-alpha-induced matrix metalloproteinase-2 expression and activity in rat vascular smooth muscle cells via the NF-kappaB pathway. Exp Ther Med 2014; 7(6): 1653-8.
  39. Lin ML, Lu YC, Chung JG, Wang SG, Lin HT, Kang SE, et al. Down-regulation of MMP-2 through the p38 MAPK-NF-kappaB-dependent pathway by aloe-emodin leads to inhibition of nasopharyngeal carcinoma cell invasion. Mol Carcinog 2010; 49(9): 783-97.
  40. Stoica G, Lungu G. Role of MMP2 in Brain Metastasis. In: Hayat MA, Editor. Tumors of the central nervous system, volume 13: Types of tumors, diagnosis, ultrasonography, surgery, brain metastasis, and general CNS diseases. Berlin, Germany: Springer Science & Business Media; 2014. p. 195-205.
  41. Boyd PJ, Doyle J, Gee E, Pallan S, Haas TL. MAPK signaling regulates endothelial cell assembly into networks and expression of MT1-MMP and MMP-2. Am J Physiol Cell Physiol 2005; 288(3): C659-C668.
  42. Qin L, Yang YB, Tuo QH, Zhu BY, Chen LX, Zhang L, et al. Effects and underlying mechanisms of curcumin on the proliferation of vascular smooth muscle cells induced by Chol: MbetaCD. Biochem Biophys Res Commun 2009; 379(2): 277-82.
  43. Jana S, Paul S, Swarnakar S. Curcumin as anti-endometriotic agent: Implication of MMP-3 and intrinsic apoptotic pathway. Biochem Pharmacol 2012; 83(6): 797-804.
  44. Schonbeck U, Libby P. CD40 signaling and plaque instability. Circ Res 2001; 89(12): 1092-103.
  45. Hakkinen T, Karkola K, Yla-Herttuala S. Macrophages, smooth muscle cells, endothelial cells, and T-cells express CD40 and CD40L in fatty streaks and more advanced human atherosclerotic lesions. Colocalization with epitopes of oxidized low-density lipoprotein, scavenger receptor, and CD16 (Fc gammaRIII). Virchows Arch 2000; 437(4): 396-405.
  46. Nagashima H, Aoka Y, Sakomura Y, Uto K, Sakuta A, Aomi S, et al. Matrix metalloproteinase 2 is suppressed by trapidil, a CD40-CD40 ligand pathway inhibitor, in human abdominal aortic aneurysm wall. J Vasc Surg 2004; 39(2): 447-53.
  47. Li X, Lu Y, Sun Y, Zhang Q. Effect of curcumin on permeability of coronary artery and expression of related proteins in rat coronary atherosclerosis heart disease model. Int J Clin Exp Pathol 2015; 8(6): 7247-53.