The role of matrix metalloproteinases in the development of atherosclerosis
Keywords:
atherosclerosis, ischemic heart disease, coronary atherosclerosis, myocardial infarction, MMP
Abstract
The physiological role of matrix metalloproteinases (MMPs) is the regulation of the extracellular matrix. During the development of a number of pathological processes, the secretion of MMPs by mesenchymal cells and immunocompetent cells increases significantly, which consistently causes matrix remodeling. The importance of MMPs is extremely latitudinous and extends to many areas of health care. MMPs are known to be involved in the process of tumor metastasis, therefore, studying their activity can help in the development of new methods for diagnosing and treating malignant neoplasms. Moreover, MMPs are associated with cartilage degradation in osteoarthritis. Their in-hibitors can be used to slow down the progression of the disease. In the aspect of cardiovascular pathology, MMPs attract attention due to their significant participation in vascular wall remodeling. The aim of the study was to clarify the role of MMPs in the pathogenesis of coronary atherosclero-sis based on the analysis of scientific literature with elements of a systematic review. Articles were searched in three online databases (PubMed, Google Scholar, and Cyberleninka). The inclusion criteria were full-text original articles in English and Russian, reports on MMPs in atherosclerosis and/or ischemic heart disease, and clinical trials. The exclusion criteria were conference abstracts, editorials, newsletters, books, and book chapters. Multiple cardiovascular pathologies, including atherosclerosis, largely depend on extracellular matrix turnover. An imbalance between MMPs and their tissue inhibitors leads to proteolytic activity dysregulation and adverse extracellular matrix remodeling, which is associated with the progression and instability of atherosclerotic plaques in the coronary arteries. Increased activity of MMPs, as well as their imbalance with tissue inhibitors of MMPs, results in remodeling of the extracellular matrix, which makes the atherosclerotic plaque more susceptible to rupture. Since excessive tissue remodeling and increased MMP activity are parts of the pathogenesis of atherosclerotic lesions, MMPs remain an attractive target for the development of anti-atherosclerotic drugs.
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References
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3. Libby P, Hansson GK. Inflammation and immunity in diseases of the arterial tree: players and layers. Circ Res. 2015 Jan 16;116(2):307-11. doi: 10.1161/CIRCRESAHA.116.301313. PMID: 25593275; PMCID: PMC4299915.
4. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115-26. doi: 10.1056/NEJM199901143400207. PMID: 9887164
5. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, et al. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int J Mol Sci. 2020;21(24):9739. Published 2020 Dec 20. doi:10.3390/ijms21249739
6. Matrix metalloproteinases, vascular remodeling, and vascular disease/ Wang X., Khalil R.A. // Adv. Pharm. – 2018. - C.241–330
7. Marino-Puertas L, Goulas T, Gomis-Rüth FX. Matrix metalloproteinases outside vertebrates. Biochim Biophys Acta Mol Cell Res. 2017 Nov;1864(11 Pt A):2026-2035. doi: 10.1016/j.bbamcr.2017.04.003. Epub 2017 Apr 7. PMID: 28392403
8. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002 Feb 22;90(3):251-62. PMID: 11861412.
9. Matrix metalloproteinases – From the cleavage data to the prediction tools and beyond/ Cieplak P., Strongin A.Y. // Biochim Biophys Acta. - 2017. - doi: 10.1016/j.bbamcr.2017.03.010.
10. Rienks M, Papageorgiou AP, Frangogiannis NG, Heymans S. Myocardial extracellular matrix: an ever-changing and diverse entity. Circ Res. 2014;114(5):872-888. doi:10.1161/CIRCRESAHA.114.302533
11. Spinale FG, Villarreal F. Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. Biochem Pharmacol. 2014;90(1):7-15. doi:10.1016/j.bcp.2014.04.011
12. Morris DR, Biros E, Cronin O, Kuivaniemi H, Golledge J. The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: a systematic review and meta-analysis. Heart. 2014;100(4):295-302. doi:10.1136/heartjnl-2013-304129
13. Vacek TP, Rehman S, Neamtu D, Yu S, Givimani S, Tyagi SC. Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms. Vasc Health Risk Manag. 2015;11:173-183. Published 2015 Feb 27. doi:10.2147/VHRM.S68415
14. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852-1866. doi:10.1161/CIRCRESAHA.114.302721
15. Johnson J. L. Matrix metalloproteinases: influence on smooth muscle cells and atherosclerotic plaque stability. Expert Review of Cardiovascular Therapy . 2007;5(2):265–282. doi: 10.1586/14779072.5.2.265.
16. Shah P. K. Biomarkers of plaque instability. Current Cardiology Reports . 2014;16 doi: 10.1007/s11886-014-0547-7.547
17. Johnson JL, Jenkins NP, Huang WC, et al. Relationship of MMP-14 and TIMP-3 expression with macrophage activation and human atherosclerotic plaque vulnerability. Mediators Inflamm. 2014;2014:276457. doi:10.1155/2014/276457
18. Kremastiotis G, Handa I, Jackson C, George S, Johnson J. Disparate effects of MMP and TIMP modulation on coronary atherosclerosis and associated myocardial fibrosis. Sci Rep. 2021;11(1):23081. Published 2021 Nov 30. doi:10.1038/s41598-021-02508-4
19. Sakakura K., Nakano M., Otsuka F., Ladich E., Kolodgie F. D., Virmani R. Pathophysiology of atherosclerosis plaque progression. Heart, Lung and Circulation. 2013;22(6):399–411. doi: 10.1016/j.hlc.2013.03.001.
20. Falk E., Nakano M., Bentzon J. F., Finn A. V., Virmani R. Update on acute coronary syndromes: the pathologists’ view. European Heart Journal. 2013;34(10):719–728. doi: 10.1093/eurheartj/ehs411
21. Loftus I. Mechanisms of plaque rupture. In: Fitridge R., Thompson M., editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists . University of Adelaide Press; 2011. p. p. 4
22. Lee S. J., Seo K. W., Yun M. R., et al. 4-Hydroxynonenal enhances MMP-2 production in vascular smooth muscle cells via mitochondrial ROS-mediated activation of the Akt/NF-κB signaling pathways. Free Radical Biology and Medicine . 2008;45(10):1487–1492. doi: 10.1016/j.freeradbiomed.2008.08.022
23. Leonarduzzi G., Chiarpotto E., Biasi F., Poli G. 4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis. Molecular Nutrition & Food Research . 2005;49(11):1044–1049. doi: 10.1002/mnfr.200500090
24. Newby A. C., Zaltsman A. B. Fibrous cap formation or destruction—the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovascular Research . 1999;41(2):345–360. doi: 10.1016/S0008-6363(98)00286-7.
25. Samah N, Ugusman A, Hamid AA, Sulaiman N, Aminuddin A. Role of Matrix Metalloproteinase-2 in the Development of Atherosclerosis among Patients with Coronary Artery Disease. Mediators Inflamm. 2023 Jul 7;2023:9715114. doi: 10.1155/2023/9715114. PMID: 37457745; PMCID: PMC10348858.
26. Massberg S, Brand K, Grüner S, Page S, Müller E, Müller I, Bergmeier W, Richter T, Lorenz M, Konrad I, Nieswandt B, Gawaz M. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med. 2002 Oct 7;196(7):887-96. doi: 10.1084/jem.20012044. PMID: 12370251; PMCID: PMC2194025
27. Simões G, Pereira T, Caseiro A. Matrix metaloproteinases in vascular pathology. Microvasc Res. 2022;143:104398. doi:10.1016/j.mvr.2022.104398
28. King SM, McNamee RA, Houng AK, Patel R, Brands M, Reed GL. Platelet dense-granule secretion plays a critical role in thrombosis and subsequent vascular remodeling in atherosclerotic mice. Circulation. 2009 Sep 1;120(9):785-91. doi: 10.1161/CIRCULATIONAHA.108.845461. Epub 2009 Aug 17. PMID: 19687360; PMCID: PMC2761818.
29. Gresele P, Falcinelli E, Sebastiano M, Momi S. Matrix Metalloproteinases and Platelet Function. Prog Mol Biol Transl Sci. 2017;147:133-165. doi: 10.1016/bs.pmbts.2017.01.002. Epub 2017 Mar 21. PMID: 28413027.
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Published
2025-06-23
How to Cite
Izmozherova N. V., Popov A. A., Shambatov M. A. oglu ., Kozhevnikova A. K. ., Melkova A. . V. The role of matrix metalloproteinases in the development of atherosclerosis // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2025. VOL. 69. № 2. PP. 117–126.
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