Pathophysiological Bases and Clinical Uses of Metalloproteases in Cardiovascular Disease: A Scoping Review
Abstract
:1. Introduction
2. Materials and Methods
- What is the existing scientific evidence on the role of MMPs in the pathophysiology of CVD, particularly in their clinical uses and their potential as future therapeutic targets?
2.1. Eligibility Criteria
2.2. Selection of Sources of Evidence
2.3. Synthesis of the Results
3. Results
3.1. Pathophysiology of ADAMTS and MMPs in Cardiovascular Disease
3.1.1. ADAMTSL 1
3.1.2. ADAMTSL 2
3.1.3. ADAMTSL 3
3.1.4. ADAMTSL 6
3.1.5. ADAMTS 7
3.1.6. ADAMS 10
3.1.7. ADAMS 12
3.1.8. ADAMTS 13
3.1.9. ADAMS 17
3.1.10. MMP 1
3.1.11. MMP 2
3.1.12. MMP 8/MMP 9
3.1.13. MMP 10
3.1.14. MT4-MMP/MMP 17
3.1.15. Neprilysin
3.1.16. CD10
3.2. Therapeutic Potential of ADAMTS and MMPs
3.2.1. ADAMTS 2, 3 and 6
3.2.2. ADAMTS 7
3.2.3. ADAMS 10
3.2.4. ADAMTS 13
3.2.5. ADAMS 17
3.2.6. MMP 1
3.2.7. MMP 2
3.2.8. MMP 8/MMP 9
3.2.9. MMP 10
3.2.10. MT4-MMP/MMP 17
3.2.11. Neprilysin
3.2.12. CD10
4. Discussion
Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Ravnskov, U.; Alabdulgader, A.; de Lorgeril, M.; Diamond, D.M.; Hama, R.; Hamazaki, T.; Hammarskjöld, B.; Harcombe, Z.; Kendrick, M.; Langsjoen, P.; et al. The new European guidelines for prevention of cardiovascular disease are misleading. Expert Rev. Clin. Pharmacol. 2020, 13, 1289–1294. [Google Scholar] [CrossRef] [PubMed]
- Bakris, G.; Ali, W.; Parati, G. ACC/AHA Versus ESC/ESH on Hypertension Guidelines: JACC Guideline Comparison. J. Am. Coll. Cardiol. 2019, 73, 3018–3026. [Google Scholar] [CrossRef]
- Wang, X.; Khalil, R.A. Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. Adv. Pharmacol. 2018, 81, 241–330. [Google Scholar]
- Amar, S.; Smith, L.; Fields, G.B. Matrix metalloproteinase collagenolysis in health and disease. Biochim. Et Biophys. Acta Mol. Cell Res. 2017, 1864, 1940–1951. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.; Peng, W.; Raffetto, J.D.; Khalil, R.A. Matrix Metalloproteinases in Remodeling of Lower Extremity Veins and Chronic Venous Disease. Prog. Mol. Biol. Transl. Sci. 2017, 267–299. [Google Scholar]
- Spinale, F.G.; Sapp, A.A. Cardiovascular Risk and Matrix Metalloproteinase Polymorphisms: Not Just a Simple Substitution. Circ. Cardiovasc. Genet. 2017, 10, e001958. [Google Scholar] [CrossRef]
- Gonçalves, P.R.; Nascimento, L.D.; Gerlach, R.F.; Rodrigues, K.E.; Prado, A.F. Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure. Pharmaceuticals 2022, 15, 920. [Google Scholar] [CrossRef] [PubMed]
- Tricco, A.C.; Lillie, E.; Zarin, W.; O’Brien, K.K.; Colquhoun, H.; Levac, D.; Moher, D.; Peters, M.D.; Horsley, T.; Weeks, L.; et al. PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation. Ann. Intern. Med. 2018, 169, 467–473. [Google Scholar] [CrossRef]
- Grudniewicz, A.; Nelson, M.; Kuluski, K.; Lui, V.; Cunningham, H.V.; Nie, J.X.; Colquhoun, H.; Wodchis, W.P.; Taylor, S.; Loganathan, M.; et al. Treatment goal setting for complex patients: Protocol for a scoping review. BMJ Open 2016, 6, e011869. [Google Scholar] [CrossRef]
- Rypdal, K.B.; Apte, S.S.; Lunde, I.G. Emerging roles for the ADAMTS-like family of matricellular proteins in cardiovascular disease through regulation of the extracellular microenvironment. Mol. Biol. Rep. 2024, 51, 280. [Google Scholar] [CrossRef]
- Mead, T.J.; Apte, S.S. ADAMTS proteins in human disorders. Matrix Biol. 2018, 71–72, 225–239. [Google Scholar] [CrossRef] [PubMed]
- Yang, S.; Gong, L.L.; Liu, L.H. Adamts-7—A new target for cardiovascular diseases treatment. Chin. Pharm. J. 2018, 53, 1536–1540. [Google Scholar]
- Hanby, H.A. Biochemistry and Physiological Functions of ADAMTS7 Metalloprotease. Adv. Biochem. 2013, 1, 43. Available online: http://www.sciencepublishinggroup.com/journal/paperinfo.aspx?journalid=110&doi=10.11648/j.ab.20130103.11 (accessed on 10 August 2023). [CrossRef] [PubMed]
- Lee, T.W.; Kao, Y.H.; Lee, T.I.; Chen, Y.J. ADAM10 modulates calcitriol-regulated RAGE in cardiomyocytes. Eur. J. Clin. Investig. 2017, 47, 675–683. Available online: http://www.ncbi.nlm.nih.gov/pubmed/28722189 (accessed on 10 August 2023). [CrossRef]
- Bourne, A.M.; Hannan, R.D.; Thomas, W. Potential roles of a disintegrin and metalloprotease proteins 10, 12, and 17 in angiotensin II-mediated transactivation of epidermal growth factor receptors. Circ. Res. 2009, 105, E46. [Google Scholar]
- Van Der Vorst, E.P.C.; Weber, C.; Donners, M.M.P.C. A Disintegrin and Metalloproteases (ADAMs) in Cardiovascular, Metabolic and Inflammatory Diseases: Aspects for Theranostic Approaches. Thromb. Haemost. 2018, 118, 1167–1175. [Google Scholar] [CrossRef]
- Solomon, E.; Li, H.; Duhachek Muggy, S.; Syta, E.; Zolkiewska, A. The role of SnoN in transforming growth factor beta1-induced expression of metalloprotease-disintegrin ADAM12. J. Biol. Chem. 2010, 285, 21969–21977. Available online: http://www.ncbi.nlm.nih.gov/pubmed/20457602 (accessed on 10 August 2023). [CrossRef]
- Eguchi, S.; Frank, G.D.; Mifune, M.; Inagami, T. Metalloprotease-dependent ErbB ligand shedding in mediating EGFR transactivation and vascular remodelling. Biochem. Soc. Trans. 2003, 31, 1198–1202. [Google Scholar] [CrossRef]
- Sonneveld, M.A.H.; Franco, O.H.; Ikram, M.A.; Hofman, A.; Kavousi, M.; de Maat, M.P.M.; Leebeek, F.W. Von Willebrand Factor, ADAMTS13, and the Risk of Mortality: The Rotterdam Study. Arter. Thromb. Vasc. Biol. 2016, 36, 2446–2451. Available online: http://www.ncbi.nlm.nih.gov/pubmed/27737864 (accessed on 10 August 2023). [CrossRef]
- Tscharre, M.; Tentzeris, I.; Vogel, B.; Freynhofer, M.K.; Egger, F.; Rohla, M.; Weiss, T.W.; Wojta, J.; Huber, K.; Farhan, S.; et al. Von Willebrand Factor and ADAMTS13 and long-term outcomes in patients undergoing percutaneous coronary intervention. Thromb. Res. 2020, 196, 31–37. [Google Scholar] [CrossRef]
- De Meyer, S. ADAMTS13, an Anti-thrombotic Protein: Evidence Outside of Thrombotic Thrombocytopenic Purpura. Blood 2019, 134 (Suppl. S1), SCI-41. [Google Scholar] [CrossRef]
- Tseng, S.C.; Kimchi-Sarfaty, C. SNPs in ADAMTS13. Pharmacogenomics 2011, 12, 1147–1160. Available online: https://www.futuremedicine.com/doi/10.2217/pgs.11.66 (accessed on 10 August 2023). [CrossRef]
- Shah, N.; Rutherford, C.; Matevosyan, K.; Shen, Y.; Sarode, R. Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP). Br. J. Haematol. 2013, 163, 514–519. Available online: http://www.ncbi.nlm.nih.gov/pubmed/24111495 (accessed on 10 August 2023). [CrossRef]
- Warlo, E.M.K.; Pettersen, A.R.; Arnesen, H.; Seljeflot, I. vWF/ADAMTS13 is associated with on-aspirin residual platelet reactivity and clinical outcome in patients with stable coronary artery disease. Thromb. J. 2017, 15, 28. Available online: https://thrombosisjournal.biomedcentral.com/articles/10.1186/s12959-017-0151-3 (accessed on 10 August 2023). [CrossRef]
- Corinaldesi, G. Effects of Low ADAMTS 13 Levels and the Role of Von Willebrand Factor in Cardiovascular Disease. Blood 2011, 118, 5320. [Google Scholar] [CrossRef]
- Warlo, E.; Bratseth, V.; Pettersen, A.; Arnesen, H.; Seljeflot, I.; Opstad, T. Genetic variation in ADAMTS13 are related to vWF levels, atrial fibrillation and cerebral ischemic events. Atherosclerosis 2022, 355, 195. [Google Scholar] [CrossRef]
- Soares, R.; Bydlowski, S.; Nascimento, N.; Thomaz, A.; Bastos, E.; Lopes, A. Plasmatic ADAMTS-13 metalloprotease and von Willebrand factor in children with cyanotic congenital heart disease. Braz. J. Med Biol. Res. 2013, 46, 375–381. [Google Scholar] [CrossRef]
- Geesala, R.; Issuree, P.D.; Maretzky, T. The Role of iRhom2 in Metabolic and Cardiovascular-Related Disorders. Front. Cardiovasc. Med. 2020, 7, 612808. [Google Scholar] [CrossRef]
- Maas, S.L.; Donners, M.M.P.C.; van der Vorst, E.P.C. ADAM10 and ADAM17, Major Regulators of Chronic Kidney Disease Induced Atherosclerosis? Int. J. Mol. Sci. 2023, 24, 7309. [Google Scholar] [CrossRef]
- Xu, J.; Mukerjee, S.; Silva-Alves, C.R.A.; Carvalho-Galvão, A.; Cruz, J.C.; Balarini, C.M.; Braga, V.A.; Lazartigues, E.; França-Silva, M.S. A disintegrin and metalloprotease 17 in the cardiovascular and central nervous systems. Front. Physiol. 2016, 7, 469. [Google Scholar] [CrossRef]
- Adu-Amankwaah, J.; Adzika, G.K.; Adekunle, A.O.; Noah, M.L.N.; Mprah, R.; Bushi, A.; Akhter, N.; Xu, Y.; Huang, F.; Chatambarara, B.; et al. The Synergy of ADAM17-Induced Myocardial Inflammation and Metabolic Lipids Dysregulation During Acute Stress: New Pathophysiologic Insights Into Takotsubo Cardiomyopathy. Front. Cardiovasc. Med. 2021, 8, 2–5. Available online: https://www.frontiersin.org/articles/10.3389/fcvm.2021.696413/full (accessed on 8 September 2023). [CrossRef] [PubMed]
- Ndoj, K.; Meurs, A.; Papaioannou, D.; Bjune, K.; Zelcer, N. The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms. Atherosclerosis 2025, 401, 119082. [Google Scholar] [CrossRef]
- Hot, A.; Lenief, V.; Cazalis, M.-A.; Miossec, P. Pathogenic role of IL-17 in endothelial dysfunction, a link between rheumatoid arthritis and atherosclerosis. Ann. Rheum. Dis. 2010, 69 (Suppl. S2), A44–A45. [Google Scholar] [CrossRef]
- Singh, M.; Benencia, F. Investigation of adipokine-induced angiogenic and proliferative responses in vascular endothelial cells: Linking angiogenesis to adipogenesis. In Embase; Singh, M., Benencia, F., Eds.; Elsevier: Amsterdam, The Netherlands, 2016. [Google Scholar]
- Bertolotto, M.; Lenglet, S.; Vuilleumier, N.; Galan, K.; Pagano, S.; Braunersreuther, V.; Pelli, G.; Pistoia, V.; Bianchi, G.; Cittadini, G.; et al. Receptor activator of NF-κB ligand (RANKL) increases the release of neutrophil products associated with coronary vulnerability. Thromb. Haemost. 2012, 107, 124–139. [Google Scholar] [CrossRef] [PubMed]
- Orbe, J.; Rodríguez, J.A.; Beloqui, O.; Belzunce, M.; Roncal, C.; Páramo, J.A. Metaloproteasa-10 (estromelisina-2): Un nuevo marcador de aterosclerosis subclínica. Clin. E Investig. En Arter. 2007, 19, 122–128. [Google Scholar] [CrossRef]
- Yip, C.; Foidart, P.; Noël, A.; Sounni, N.E. MT4-MMP: The GPI-anchored membrane-type matrix metalloprotease with multiple functions in diseases. Int. J. Mol. Sci. 2019, 20, 354. [Google Scholar] [CrossRef] [PubMed]
- Reddy, Y.N.; Lyer, S.R.; Scott, C.G.; Rodeheffer, R.J.; Bailey, K.; Redfield, M.M.; Burnett, J.C.; Pereira, N.L. Abstract 16084: Serum Neprilysin and Its Relationship to Cardiovascular Disease in the General Population. AHA 2018, 138. Available online: https://www.ahajournals.org/doi/10.1161/circ.138.suppl_1.16084 (accessed on 8 September 2023).
- Reddy, Y.N.V.; Iyer, S.R.; Scott, C.G.; Rodeheffer, R.J.; Bailey, K.; Jenkins, G.; Batzler, A.; Redfield, M.M.; Burnett, J.C., Jr.; Pereira, N.L. Soluble Neprilysin in the General Population: Clinical Determinants and Its Relationship to Cardiovascular Disease. Available online: https://www.ahajournals.org/doi/10.1161/JAHA.119.012943 (accessed on 8 September 2023).
- Wang, S.; Xiao, Y.; An, X.; Luo, L.; Gong, K.; Yu, D. A comprehensive review of the literature on CD10: Its function, clinical application, and prospects. Front. Pharmacol. 2024, 15, 1336310. [Google Scholar] [CrossRef]
- Allen, S.; Liu, Y.-G.; Scott, E. Engineering Nanomaterials to Address Cell-Mediated Inflammation in Atherosclerosis. Regen. Eng. Transl. Med. 2016, 2, 37–50. Available online: http://link.springer.com/10.1007/s40883-016-0012-9 (accessed on 8 September 2023). [CrossRef]
- Moss, S.; Subramanian, V.; Acharya, K.R. Crystal structure of peptide-bound neprilysin reveals key binding interactions. FEBS Lett. 2020, 594, 327–336. Available online: http://www.ncbi.nlm.nih.gov/pubmed/31514225 (accessed on 8 September 2023). [CrossRef]
- Nicolaou, A.; Zhao, Z.; Northoff, B.H.; Sass, K.; Herbst, A.; Kohlmaier, A.; Chalaris, A.; Wolfrum, C.; Weber, C.; Steffens, S.; et al. Adam17 Deficiency promotes atherosclerosis by enhanced TNFR2 signaling in Mice. Arterioscler. Thromb. Vasc. Biol. 2017, 37, 247–257. [Google Scholar] [CrossRef] [PubMed]
- Suzuki, H.; Eguchi, S. Growth factor receptor transactivation in mediating end organ damage by angiotensin II. Hypertension 2006, 47, 339–340. [Google Scholar] [CrossRef] [PubMed]
- Altieri, P.; Bertolotto, M.; Fabbi, P.; Sportelli, E.; Balbi, M.; Santini, F.; Brunelli, C.; Canepa, M.; Montecucco, F.; Ameri, P. Thrombin induces protease-activated receptor 1 signaling and activation of human atrial fibroblasts and dabigatran prevents these effects. Int. J. Cardiol. 2018, 271, 219–227. Available online: http://www.ncbi.nlm.nih.gov/pubmed/29801760 (accessed on 8 September 2023). [CrossRef] [PubMed]
Molecule’s Name | Pathophysiology in CVD | Therapeutic Target |
---|---|---|
ADAMTSL 1 | Associated with cardiac fibrosis and ECM remodeling. | |
ADAMTSL 2 | Regulates TGFB, reduces its activation and it is linked to dysplasias. | TGFB inhibitor, fibrosis biomarker. |
ADAMTSL 3 | Cardioprotective, reduces TGFB and collagen. | |
ADAMTSL 6 | Inhibits TGFB, affects aortic dilation and blood pressure. | |
ADAMTSL 7 | Pro-atherogenic, degradates COMP. | Therapeutic inhibition via miRNA or blockers. |
ADAMTSL 10 | Regulated by calcitriol, activates sRAGE, involved in inflammation. | Inhibition reduces inflammation, calcitriol-based therapies. |
ADAMTSL 12 | Associated with cardiac hypertrophy, vascular remodeling. | |
ADAMTSL 13 | Regulates VWF, low levels = ↑ cardiovascular mortality. | Recombinant rADAMTS13 in TTP, biomarker for MI and stroke. |
ADAMTSL 17 | Promotes inflammation and remodeling, activated by catecholamines. | Inhibition reduces inflammation, modulated by Rhom1-2. |
MMP 1 | Degradates collagen I and LDLr, linked to plaque rupture. | Inhibition enhances LDL uptake, possible CV prevention. |
MMP 2 | Induced by IL-17, involved in angiogenesis and adipogenesis. | Nanomaterials reduce its expression (anti-inflammatory). |
MMP 8/9 | Associated with RANKL, coronary calcification. | Inhibition via ERK1/2 and PI3K/Akt pathways. |
MMP 10 | Vascular remodeling, unstable plaques, inflammation. | Inhibition may prevent atherosclerotic progression. |
MMP 17/MT4-MPP | Remodeling, inflammation, aneurysms, cell migration. | Potential therapeutic target in atherosclerosis. |
Neprilysin | Degrades natriuretic peptides, promotes vasoconstriction. | Inhibition has antihypertensive effect. |
CD10 | Degrades both vasodilators and vasoconstrictors. | Inhibition enhances natriuretic peptide effects, useful in heart failure. |
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Olarte Bermúdez, L.M.; Karduss Preciado, C.; Ángel, J.M.E.; Santos Granados, A.M.; Martínez Lozano, J.C.; Pacheco Cuentas, C.A.; Díaz Quijano, D.M. Pathophysiological Bases and Clinical Uses of Metalloproteases in Cardiovascular Disease: A Scoping Review. Cardiogenetics 2025, 15, 14. https://doi.org/10.3390/cardiogenetics15020014
Olarte Bermúdez LM, Karduss Preciado C, Ángel JME, Santos Granados AM, Martínez Lozano JC, Pacheco Cuentas CA, Díaz Quijano DM. Pathophysiological Bases and Clinical Uses of Metalloproteases in Cardiovascular Disease: A Scoping Review. Cardiogenetics. 2025; 15(2):14. https://doi.org/10.3390/cardiogenetics15020014
Chicago/Turabian StyleOlarte Bermúdez, Laura Manuela, Camila Karduss Preciado, Julián Manuel Espitia Ángel, Ana María Santos Granados, Julio Cesar Martínez Lozano, Carlos Alberto Pacheco Cuentas, and Diana Marcela Díaz Quijano. 2025. "Pathophysiological Bases and Clinical Uses of Metalloproteases in Cardiovascular Disease: A Scoping Review" Cardiogenetics 15, no. 2: 14. https://doi.org/10.3390/cardiogenetics15020014
APA StyleOlarte Bermúdez, L. M., Karduss Preciado, C., Ángel, J. M. E., Santos Granados, A. M., Martínez Lozano, J. C., Pacheco Cuentas, C. A., & Díaz Quijano, D. M. (2025). Pathophysiological Bases and Clinical Uses of Metalloproteases in Cardiovascular Disease: A Scoping Review. Cardiogenetics, 15(2), 14. https://doi.org/10.3390/cardiogenetics15020014