Study of Matrix Metalloproteinases and Their Inhibitors in Blood Serum of Healthy Men of Different Ages Exposed to Risk Factors

Aging is an irreversible process that proceeds individually in each case. It is known that the matrix metalloproteinase (MMP) system is involved in processes associated with aging. The aim of the study was to investigate changes in the levels of MMPs (MMP-1, MMP-2, MMP-3, MMP-7), their tissue inhibitors (TIMP-1, TIMP-2), and complexes MMP-9/TIMP-1, MMP-9/TIMP-2 involved in vascular wall remodeling in conditionally healthy men of different age groups, taking into account modifiable risk factors (RF) for cardiovascular diseases (CVD). Materials and methods. The study included 151 men: 30 (20%) young adults; 41 (27%) middle-aged; 62 (41%) elderly; and 18 (12%) senile. The levels of MMP-1, -2, -3, -7, -9, TIMP-1, -2, as well as MMP-9/TIMP-1 and MMP-9/TIMP-2 complexes were determined. Concentrations were calculated using calibration curves in a computer program (ng/ml or pg/ml). Additionally, MMP/TIMP ratios were calculated (e.g., MMP-3/TIMP-1, MMP-3/TIMP-2). Results. With age, MMP-1 and MMP-3 predominate in men, while in the elderly group, levels of MMP-9/TIMP-2 complexes are elevated. Smoking and other CVD risk factors significantly increase the levels of MMP-1, -2, -3, and TIMP-1 across all age groups, while in elderly individuals, the formation of MMP-9/TIMP-2 complexes decreases. Levels of MMP-9 and MMP-9/TIMP-2 complexes decrease with age; however, the presence of risk factors, especially smoking, increases these indicators in elderly and senile age groups. TIMP-1 levels change in a wave-like pattern with age, but risk factors and smoking consistently increase them across all groups. Conclusion. The study revealed a correlation between CVD risk factors and MMP levels in conditionally healthy men of different age groups. Multidirectional changes in MMPs and TIMPs were established. The most significant indicators show a decrease in MMP-9 and MMP-9/TIMP-2 levels with age, their increase in the presence of risk factors (especially smoking) in elderly and senile age groups, as well as wave-like dynamics of TIMP-1 with a consistent increase under the influence of risk factors.

1. Berstein L.M., Tsyrlina E.V. Hypothalamic-Pituitary System: Age and Major Non-Infectious Diseases (Malignant Neoplasms of Hormone-Dependent Tissues, Cardiovascular Pathology and Type 2 Diabetes). Russian Journal of Physiology. 106(6):667–682. (In Russ.) https://doi.org/10.31857/S0869813920060023

2. Bassiouni W, Ali MAM, Schulz R. Multifunctional intracellular matrix metalloproteinases: implications in disease. FEBS J. 2021 Dec;288(24):7162-7182. https://doi.org/10.1111/febs.15701. Epub 2021 Jan 22. PMID: 33405316.

3. Simões G, Pereira T, Caseiro A. Matrix metaloproteinases in vascular pathology. Microvasc Res. 2022 Sep;143:104398. https://doi.org/10.1016/j.mvr.2022.104398. Epub 2022 Jun 6. PMID: 35671836.

4. Avdeeva I., Burko N., Kvasova O. et al. Early vascular aging: pathogenesis and possibilities of drug correction. Vrach. 2019; 30 (12): 10–13. (In Russ.) https://doi.org/10.29296/25877305-2019-12-03

5. Stakhneva E.M., Kashtanova E.V., Polonskaya Ya.V., Shramko V.S., Ragino Yu.I. Mechanisms of vascular aging. Bulletin of Siberian Medicine. 2022;21(2):186–194. (In Russ.) https://doi.org/10.20538/1682-0363-2022-2-186-194

6. Sergienko V.B., Ansheles A.A., Sergienko I.V., Boytsov S.A. Relationship of obesity, low-density lipoprotein cholesterol and myocardial perfusion in patients with risk factors and without atherosclerotic cardiovascular diseases. Cardiovascular Therapy and Prevention. 2021;20(2):2734. (In Russ.) https://doi.org/10.15829/1728-8800-2021-2734

7. Chmelova M., Androvic P., Kirdajova D. et al. A view of the genetic and proteomic profile of extracellular matrix molecules in aging and stroke. Frontiers of Cellural Neuroscience. 2023;17:1296455.

8. Ungvari Z, Tarantini S, Sorond F, Merkely B, Csiszar A. Mechanisms of Vascular Aging, A Geroscience Perspective: JACC Focus Seminar. J Am Coll Cardiol. 2020 Mar 3;75(8):931-941. https://doi.org/10.1016/j.jacc.2019.11.061. PMID: 32130929; PMCID: PMC8559983.

9. Garvin P, Nilsson L, Carstensen J, Jonasson L, Kristenson M. Circulating matrix metalloproteinase-9 is associated with cardiovascular risk factors in a middle-aged normal population. PLoS One. 2008 Mar 12;3(3):e1774. https://doi.org/10.1371/journal.pone.0001774. PMID: 18335048; PMCID: PMC2258002.

10. Cancemi P, Aiello A, Accardi G, Caldarella R, Candore G, Caruso C, Ciaccio M, Cristaldi L, Di Gaudio F, Siino V, Vasto S. The Role of Matrix Metalloproteinases (MMP-2 and MMP-9) in Ageing and Longevity: Focus on Sicilian Long-Living Individuals (LLIs). Mediators Inflamm. 2020 May 5;2020:8635158. https://doi.org/10.1155/2020/8635158. PMID: 32454796; PMCID: PMC7222606.

11. Longtine AG, Venkatasubramanian R, Zigler MC, Lindquist AJ, Mahoney SA, Greenberg NT, VanDongen NS, Ludwig KR, Moreau KL, Seals DR, Clayton ZS. Female C57BL/6N mice are a viable model of aortic aging in women. Am J Physiol Heart Circ Physiol. 2023 Jun 1;324(6):H893-H904. https://doi.org/10.1152/ajpheart.00120.2023. Epub 2023 Apr 28. PMID: 37115626; PMCID: PMC10202480.

12. Knox A. Arterial Aging, Metalloproteinase Regulation, and the Potential of Resistance Exercise. Current Cardiology Reviews. 2018;14(4):227–232.

13. Iannarelli N.J., MacNeil A.J., Dempster K.S., Wade T.J. et al. Serum MMP-3 and its association with central arterial stiffness among young adults is moderated by smoking and BMI. Physiology Report. 2021;9(11):e14920.

14. Mondal S, Adhikari N, Banerjee S, Amin SA, Jha T. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur J Med Chem. 2020 May 15;194:112260. https://doi.org/10.1016/j.ejmech.2020.112260. Epub 2020 Mar 21. Erratum in: Eur J Med Chem. 2020 Nov 1;205:112642. https://doi.org/10.1016/j.ejmech.2020.112642. PMID: 32224379.