r-n-jРоссийский неврологический журналRussian neurological journal2658-79472686-7192МИА10.30629/2658-7947-2024-29-3-5-15r-n-j-572Research ArticleОБЗОРЫREVIEWSРоль матриксных металлопротеиназ в патогенетических механизмах ишемического инсультаThe role of matrix metalloproteinases in the pathogenetic mechanisms of ischemic strokehttps://orcid.org/0000-0003-4968-4012КучероваК. С.KucherovaK. S.

Томск

Tomsk

kristyajka@ya.ruhttps://orcid.org/0000-0003-1911-166XКоролёваЕ. С.KorolevaE. S.

Томск

Tomsk

kattorina@list.ruhttps://orcid.org/0000-0002-4140-3223АлифироваВ. М.AlifirovaV. M.

Томск

Tomsk

v_alifirova@mail.ruСибирский государственный медицинский университетРоссияSiberian State Medical UniversityRussian Federation202423072024293515Copyright © Кучерова К.С., Королёва Е.С., Алифирова В.М., 20242024Кучерова К.С., Королёва Е.С., Алифирова В.М.Kucherova K.S., Koroleva E.S., Alifirova V.M.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.r-n-j.com/jour/article/view/572

   Современные представления о механизмах патогенеза ишемического инсульта расширились в результате исследования процессов нейровоспаления, немаловажную роль в котором играют матриксные металлопротеиназы (ММП). В обзоре охарактеризованы основные типы ММП, приведены актуальные данные о патофизиологической роли данной группы протеаз при острой ишемии головного мозга, имеющих разнонаправленное действие в зависимости от стадии заболевания. Клинические исследования, посвященные оценке роли ММП при ишемическом инсульте, в большинстве случаев основаны на экспериментальных моделях, и результаты являются неоднозначными, что определяется многогранностью их действия. ММП являются важным регулятором воспалительных процессов, проницаемости гематоэнцефалического барьера и, как следствие, отека головного мозга. Однако доказано положительное влияние ММП в процессах ангиогенеза, нейрогенеза и нейропластичности. Таким образом, дальнейшее изучение ММП является актуальным с точки зрения их роли в функциональном восстановлении после ишемического инсульта.

   Modern understanding of the mechanisms of the pathogenesis of ischemic stroke has expanded due to the study of neuroinfl ammation processes, in which matrix metalloproteinases (MMPs) play an important role. This literature review describes the main types of MMPs and provides current data on the pathophysiological role of this group of proteases in acute cerebral ischemia, which have multidirectional eff ects depending on the stage of the disease. Clinical studies assessing the role of MMPs in ischemic stroke are in most cases based on experimental models, and their results are ambiguous, which is determined by the versatility of their actions. MMPs are an important regulator of infl ammatory processes, the permeability of the blood-brain barrier and, as a consequence, cerebral edema. However, the positive eff ect of MMPs in the processes of angiogenesis, neurogenesis and neuroplasticity has been proven. Thus, further study of MMPs is relevant from the point of view of their role in functional recovery after ischemic stroke.

ишемический инсультматриксные металлопротеиназынейровоспалениегеморрагическая трансформацияангиогенезнейрорегенерацияischemic strokematrix metalloproteinasesneuroinfl ammationhemorrhagic transformationangiogenesisneuroregenerationИсследование выполнено без финансовой поддержкиThe study had no sponsorshipReferencesFeigin V.L, Brainin M, Norrving B, Martins S, Sacco R.L, Hacke W, et al. World Stroke Organization (WSO): Global Stroke Fact Sheet 2022. International journal of stroke. 2022;17(1):18–29. doi: 10.1177/17474930211065917Feigin V.L, Brainin M, Norrving B, Martins S, Sacco R.L, Hacke W, et al. World Stroke Organization (WSO): Global Stroke Fact Sheet 2022. International journal of stroke. 2022;17(1):18–29. doi: 10.1177/17474930211065917GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795–820. doi: 10.1016/S1474-4422(21)00252-0GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795–820. doi: 10.1016/S1474-4422(21)00252-0Суслина З.А., Варакин Ю.Я. Эпидемиологические аспекты изучения инсульта. Время подводить итоги. Анналы клинической и экспериментальной неврологии. 2007;1(2):22–28. URL: https://cyberleninka.ru/article/n/epidemiologicheskie-aspekty-izucheniya-insulta-vremya-podvodit-itogi?ysclid=lyy6xdxhjt361794254Suslina Z.A., Varakin Y.Y. Epidemiological aspects of the study of stroke. Time to take stock. Annals of Clinical and Experimental Neurology. 2007;1(2):22–28. (In Russ.). URL: https://cyberleninka.ru/article/n/epidemiologicheskie-aspekty-izucheniya-insulta-vremya-podvodit-itogi?ysclid=lyy6xdxhjt361794254Скворцова В.И., Стаховская Л.В., Айриян Н.Ю. Эпидемиология инсульта в Российской Федерации. Системные гипертензии. 2005;2(1):10–12. doi: 10.26442/SG28725Skvortsova V.I., Stakhovskaya L.V., Ayriyan N.Y. Epidemiology of stroke in the Russian Federation. Systemic Hypertension. 2005;2(1):10–12. (In Russ.). doi: 10.26442/SG28725Jayaraj R.L., Azimullah S., Beiram R., Jalal F.Y., Rosenberg G.A. Neuroinfl ammation: friend and foe for ischemic stroke. J Neuro-inflammation. 2019;16(1):142. doi: 10.1186/s12974-019-1516-2Jayaraj R.L., Azimullah S., Beiram R., Jalal F.Y., Rosenberg G.A. Neuroinfl ammation: friend and foe for ischemic stroke. J Neuro-inflammation. 2019;16(1):142. doi: 10.1186/s12974-019-1516-2Candelario-Jalil E., Dijkhuizen R.M., Magnus T. Neuroinfl ammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities. Stroke. 2022;53(5):1473–1486. doi: 10.1161/STROKEAHA.122.036946Candelario-Jalil E., Dijkhuizen R.M., Magnus T. Neuroinfl ammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities. Stroke. 2022;53(5):1473–1486. doi: 10.1161/STROKEAHA.122.036946Qin C., Yang S., Chu Y.H., Zhang H., Pang X.W., Chen L. et al. Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022;7(1):215. doi: 10.1038/s41392-022-01064-1Qin C., Yang S., Chu Y.H., Zhang H., Pang X.W., Chen L. et al. Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022;7(1):215. doi: 10.1038/s41392-022-01064-1Ji Y., Gao Q., Ma Y., Wang F., Tan X., Song D. et al. An MMP-9 exclusive neutralizing antibody attenuates blood-brain barrier breakdown in mice with stroke and reduces stroke patient-derived MMP-9 activity. Pharmacol. Res. 2023;190:106720. doi: 10.1016/j.phrs.2023.106720Ji Y., Gao Q., Ma Y., Wang F., Tan X., Song D. et al. An MMP-9 exclusive neutralizing antibody attenuates blood-brain barrier breakdown in mice with stroke and reduces stroke patient-derived MMP-9 activity. Pharmacol. Res. 2023;190:106720. doi: 10.1016/j.phrs.2023.106720Tirandi A., Sgura C., Carbone F., Montecucco F., Liberale L. Inflammatory biomarkers of ischemic stroke. Intern Emerg Med. 2023;18(3):723–732. doi: 10.1007/s11739-023-03201-2Tirandi A., Sgura C., Carbone F., Montecucco F., Liberale L. Inflammatory biomarkers of ischemic stroke. Intern Emerg Med. 2023;18(3):723–732. doi: 10.1007/s11739-023-03201-2Montellano F.A., Ungethüm K., Ramiro L., Nacu A., Hellwig S., Fluri F. et al. Role of Blood-Based Biomarkers in Ischemic Stroke Prognosis: A Systematic Review. Stroke. 2021;52(2):543–551. doi: 10.1161/STROKEAHA.120.029232Montellano F.A., Ungethüm K., Ramiro L., Nacu A., Hellwig S., Fluri F. et al. Role of Blood-Based Biomarkers in Ischemic Stroke Prognosis: A Systematic Review. Stroke. 2021;52(2):543–551. doi: 10.1161/STROKEAHA.120.029232Bai M., Sun R., Cao B., Feng J., Wang J. Monocyte-related cytokines/chemokines in cerebral ischemic stroke. CNS Neurosci Ther. 2023;29(12):3693–3712. doi: 10.1111/cns.14368Bai M., Sun R., Cao B., Feng J., Wang J. Monocyte-related cytokines/chemokines in cerebral ischemic stroke. CNS Neurosci Ther. 2023;29(12):3693–3712. doi: 10.1111/cns.14368Yang Y., Rosenberg G.A. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res. 2015;1623:30–8. doi: 10.1016/j.brainres.2015.04.024Yang Y., Rosenberg G.A. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res. 2015;1623:30–8. doi: 10.1016/j.brainres.2015.04.024Kimura-Ohba S., Yang Y. Oxidative DNA Damage Mediated by Intranuclear MMP Activity Is Associated with Neuronal Apoptosis in Ischemic Stroke. Oxid Med Cell Longev. 2016;2016:6927328. doi: 10.1155/2016/6927328Kimura-Ohba S., Yang Y. Oxidative DNA Damage Mediated by Intranuclear MMP Activity Is Associated with Neuronal Apoptosis in Ischemic Stroke. Oxid Med Cell Longev. 2016;2016:6927328. doi: 10.1155/2016/6927328Schönbeck U., Mach F., Libby P. Generation of biologically active IL-1β by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1β processing. Journal of Immunology. 1998;161(7):3340–3346. doi: 10.4049/jimmunol.161.7.3340Schönbeck U., Mach F., Libby P. Generation of biologically active IL-1β by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1β processing. Journal of Immunology. 1998;161(7):3340–3346. doi: 10.4049/jimmunol.161.7.3340Berta T., Liu T., Liu Y.C., Xu Z.Z., Ji R.R. Acute morphine activates satellite glial cells and up-regulates IL-1β in dorsal root ganglia in mice via matrix metalloprotease-9. Molecular Pain. 2012;8, article 18. doi: 10.1186/1744-8069-8-18Berta T., Liu T., Liu Y.C., Xu Z.Z., Ji R.R. Acute morphine activates satellite glial cells and up-regulates IL-1β in dorsal root ganglia in mice via matrix metalloprotease-9. Molecular Pain. 2012;8, article 18. doi: 10.1186/1744-8069-8-18Costru-Tasnic E., Gavriliuc M., Manole E. The importance of matrix metalloproteinases in the prognosis of acute ischemic stroke patients. Mold Med J. 2021;62(3):44–49. doi: 10.52418/moldovan-med-j.64-3.21.09Costru-Tasnic E., Gavriliuc M., Manole E. The importance of matrix metalloproteinases in the prognosis of acute ischemic stroke patients. Mold Med J. 2021;62(3):44–49. doi: 10.52418/moldovan-med-j.64-3.21.09Chang J.J., Stanfi ll A., Pourmotabbed T. The Role of Matrix Metalloproteinase Polymorphisms in Ischemic Stroke. Int J Mol Sci. 2016;17(8):1323. doi: 10.3390/ijms17081323Chang J.J., Stanfi ll A., Pourmotabbed T. The Role of Matrix Metalloproteinase Polymorphisms in Ischemic Stroke. Int J Mol Sci. 2016;17(8):1323. doi: 10.3390/ijms17081323Adibhatla R.M., Hatcher J.F. Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets. 2008;7(3):243–53. doi: 10.2174/187152708784936608Adibhatla R.M., Hatcher J.F. Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets. 2008;7(3):243–53. doi: 10.2174/187152708784936608Cui N., Hu M., Khalil R.A. Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci. 2017;147(617):1–73. doi: 10.1016/bs.pmbts.2017.02.005Cui N., Hu M., Khalil R.A. Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci. 2017;147(617):1–73. doi: 10.1016/bs.pmbts.2017.02.005Ågren M.S., Auf dem Keller U. Matrix Metalloproteinases: How Much Can They Do? Int J Mol Sci. 2020;21(8):2678. doi: 10.3390/ijms21082678Ågren M.S., Auf dem Keller U. Matrix Metalloproteinases: How Much Can They Do? Int J Mol Sci. 2020;21(8):2678. doi: 10.3390/ijms21082678Romi F., Helgeland G., Gilhus N.E. Serum levels of matrix metalloproteinases: implications in clinical neurology. Eur Neurol. 2012;67(2):121–8. doi: 10.1159/000334862Romi F., Helgeland G., Gilhus N.E. Serum levels of matrix metalloproteinases: implications in clinical neurology. Eur Neurol. 2012;67(2):121–8. doi: 10.1159/000334862Almutairi S., Kalloush H.M., Manoon N.A., Bardaweel S.K. Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023). Molecules. 2023;28(14):5567. doi: 10.3390/molecules28145567Almutairi S., Kalloush H.M., Manoon N.A., Bardaweel S.K. Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023). Molecules. 2023;28(14):5567. doi: 10.3390/molecules28145567Boziki M., Grigoriadis N. An Update on the Role of Matrix Metalloproteinases in the Pathogenesis of Multiple Sclerosis. Med Chem. 2018;14(2):155–169. doi: 10.2174/1573406413666170906122803Boziki M., Grigoriadis N. An Update on the Role of Matrix Metalloproteinases in the Pathogenesis of Multiple Sclerosis. Med Chem. 2018;14(2):155–169. doi: 10.2174/1573406413666170906122803Sánchez-Torres J.L., Yescas-Gómez P., Torres-Romero J., Espinosa O.R., Canovas L.L., Tecalco-Cruz Á.C., et al. Matrix metalloproteinases deregulation in amyotrophic lateral sclerosis. J Neurol Sci. 2020;419:117175. doi: 10.1016/j.jns.2020.117175Sánchez-Torres J.L., Yescas-Gómez P., Torres-Romero J., Espinosa O.R., Canovas L.L., Tecalco-Cruz Á.C., et al. Matrix metalloproteinases deregulation in amyotrophic lateral sclerosis. J Neurol Sci. 2020;419:117175. doi: 10.1016/j.jns.2020.117175Zipfel P., Rochais C., Baranger K., Rivera S., Dallemagne P. Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges. J Med Chem. 2020;63(19):10705–10725. doi: 10.1021/acs.jmedchem.0c00352Zipfel P., Rochais C., Baranger K., Rivera S., Dallemagne P. Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges. J Med Chem. 2020;63(19):10705–10725. doi: 10.1021/acs.jmedchem.0c00352Montaner J., Ramiro L., Simats A., Hernández-Guillamon M., Delgado P., Bustamante A., Rosell A. Matrix metalloproteinases and ADAMs in stroke. Cellular and Molecular Life Sciences. 2019;76(16):3117–3140. doi: 10.1007/s00018-019-03175-5Montaner J., Ramiro L., Simats A., Hernández-Guillamon M., Delgado P., Bustamante A., Rosell A. Matrix metalloproteinases and ADAMs in stroke. Cellular and Molecular Life Sciences. 2019;76(16):3117–3140. doi: 10.1007/s00018-019-03175-5Planas A.M., Solé S., Justicia C. Expression and activation of matrix metalloproteinase-2 and -9 in rat brain after transient focal cerebral ischemia. Neurobiol Dis. 2001;8(5):834–46. doi: 10.1006/nbdi.2001.0435Planas A.M., Solé S., Justicia C. Expression and activation of matrix metalloproteinase-2 and -9 in rat brain after transient focal cerebral ischemia. Neurobiol Dis. 2001;8(5):834–46. doi: 10.1006/nbdi.2001.0435Cuadrado E., Rosell A., Borrell-Pagès M., García-Bonilla L., Hernández-Guillamon M., Ortega-Aznar A., Montaner J. Matrix metalloproteinase-13 is activated and is found in the nucleus of neural cells after cerebral ischemia. J Cereb Blood Flow Metab. 2009;29(2):398–410. doi: 10.1038/jcbfm.2008.130Cuadrado E., Rosell A., Borrell-Pagès M., García-Bonilla L., Hernández-Guillamon M., Ortega-Aznar A., Montaner J. Matrix metalloproteinase-13 is activated and is found in the nucleus of neural cells after cerebral ischemia. J Cereb Blood Flow Metab. 2009;29(2):398–410. doi: 10.1038/jcbfm.2008.130Chelluboina B., Klopfenstein J.D., Pinson D.M., Wang D.Z., Vemuganti R., Veeravalli K.K. Matrix Metalloproteinase-12 Induces Blood-Brain Barrier Damage After Focal Cerebral Ischemia. Stroke. 2015;46(12):3523–31. doi: 10.1161/STROKEAHA.115.011031Chelluboina B., Klopfenstein J.D., Pinson D.M., Wang D.Z., Vemuganti R., Veeravalli K.K. Matrix Metalloproteinase-12 Induces Blood-Brain Barrier Damage After Focal Cerebral Ischemia. Stroke. 2015;46(12):3523–31. doi: 10.1161/STROKEAHA.115.011031Cuadrado E., Ortega L., Hernández-Guillamon M., Penalba A., Fernández-Cadenas I., Rosell A., Montaner J. Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release. J Leukoc Biol. 2008;84(1):207–14. doi: 10.1189/jlb.0907606Cuadrado E., Ortega L., Hernández-Guillamon M., Penalba A., Fernández-Cadenas I., Rosell A., Montaner J. Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release. J Leukoc Biol. 2008;84(1):207–14. doi: 10.1189/jlb.0907606Turner R.J., Sharp F.R. Implications of MMP-9 for blood-brain barrier disruption and hemorrhagic transformation following ischemic stroke. Front Cell Neurosci. 2016;10:1–13. doi: 10.3389/fncel.2016.00056Turner R.J., Sharp F.R. Implications of MMP-9 for blood-brain barrier disruption and hemorrhagic transformation following ischemic stroke. Front Cell Neurosci. 2016;10:1–13. doi: 10.3389/fncel.2016.00056Thomsen M.S., Routhe L.J., Moos T. The vascular basement membrane in the healthy and pathological brain. J Cereb Blood Flow Metab. 2017;37(10):3300–17. doi: 10.1177/0271678X17722436Thomsen M.S., Routhe L.J., Moos T. The vascular basement membrane in the healthy and pathological brain. J Cereb Blood Flow Metab. 2017;37(10):3300–17. doi: 10.1177/0271678X17722436Maestrini I., Ducroquet A., Moulin S., Leys D., Cordonnier C., Bordet R. Blood biomarkers in the early stage of cerebral ischemia. Rev Neurol (Paris). 2016;172(3):198–219. doi: 10.1016/j.neurol.2016.02.003Maestrini I., Ducroquet A., Moulin S., Leys D., Cordonnier C., Bordet R. Blood biomarkers in the early stage of cerebral ischemia. Rev Neurol (Paris). 2016;172(3):198–219. doi: 10.1016/j.neurol.2016.02.003Yang C., Hawkins K.E., Doré S., Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol. 2019;316(2):135–153. doi: 10.1152/ajpcell.00136.2018Yang C., Hawkins K.E., Doré S., Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol. 2019;316(2):135–153. doi: 10.1152/ajpcell.00136.2018Liu J., Jin X., Liu K.J., Liu W. Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage. J Neurosci. 2012;32:3044–3057. doi: 10.1523/JNEUROSCI.6409-11.2012Liu J., Jin X., Liu K.J., Liu W. Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage. J Neurosci. 2012;32:3044–3057. doi: 10.1523/JNEUROSCI.6409-11.2012Park K.P., Rosell A., Foerch C., Xing C., Kim W.J., Lee S. et al. Plasma and brain matrix metalloproteinase-9 after acute focal cerebral ischemia in rats. Stroke. 2009;40:2836–2842. doi: 10.1161/STROKEAHA.109.554824Park K.P., Rosell A., Foerch C., Xing C., Kim W.J., Lee S. et al. Plasma and brain matrix metalloproteinase-9 after acute focal cerebral ischemia in rats. Stroke. 2009;40:2836–2842. doi: 10.1161/STROKEAHA.109.554824Asahi M., Sumii T., Fini M.E., Itohara S., Lo E.H. Matrix metalloproteinase 2 gene knockout has no eff ect on acute brain injury after focal ischemia. Neuroreport. 2001;12:3003–3007. doi: 10.1097/00001756-200109170-00050Asahi M., Sumii T., Fini M.E., Itohara S., Lo E.H. Matrix metalloproteinase 2 gene knockout has no eff ect on acute brain injury after focal ischemia. Neuroreport. 2001;12:3003–3007. doi: 10.1097/00001756-200109170-00050Lu A., Suofu Y., Guan F., Broderick J.P., Wagner K.R., Clark J.F. Matrix metalloproteinase-2 deletions protect against hemorrhagic transformation after 1 h of cerebral ischemia and 23 h of reperfusion. Neuroscience. 2013;253:361–367. doi: 10.1016/j.neuroscience.2013.08.068Lu A., Suofu Y., Guan F., Broderick J.P., Wagner K.R., Clark J.F. Matrix metalloproteinase-2 deletions protect against hemorrhagic transformation after 1 h of cerebral ischemia and 23 h of reperfusion. Neuroscience. 2013;253:361–367. doi: 10.1016/j.neuroscience.2013.08.068Sarvari S., Moakedi F., Hone E., Simpkins J.W., Ren X. Mechanisms in blood-brain barrier opening and metabolism-challenged cerebrovascular ischemia with emphasis on ischemic stroke. Metab Brain Dis. 2020;35(6):851–68. doi: 10.1007/s11011-020-00573-8Sarvari S., Moakedi F., Hone E., Simpkins J.W., Ren X. Mechanisms in blood-brain barrier opening and metabolism-challenged cerebrovascular ischemia with emphasis on ischemic stroke. Metab Brain Dis. 2020;35(6):851–68. doi: 10.1007/s11011-020-00573-8Lakhan S.E., Kirchgessner A., Tepper D., Leonard A. Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front Neurol. 2013;4:1–15. doi: 10.3389/fneur.2013.00032Lakhan S.E., Kirchgessner A., Tepper D., Leonard A. Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front Neurol. 2013;4:1–15. doi: 10.3389/fneur.2013.00032Suzuki Y., Nagai N., Umemura K., Collen D., Lijnen H.R. Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice. J Thromb Haemost. 2007;5:1732–1739. doi: 10.1111/j.1538-7836.2007.02628.xSuzuki Y., Nagai N., Umemura K., Collen D., Lijnen H.R. Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice. J Thromb Haemost. 2007;5:1732–1739. doi: 10.1111/j.1538-7836.2007.02628.xChelluboina B., Klopfenstein J.D., Pinson D.M., Wang D.Z., Vemuganti R., Veeravalli K.K. Matrix metalloproteinase-12 induces blood-brain barrier damage after focal cerebral ischemia. Stroke. 2015;46:3523–3531. doi: 10.1161/STROKEAHA.115.011031Chelluboina B., Klopfenstein J.D., Pinson D.M., Wang D.Z., Vemuganti R., Veeravalli K.K. Matrix metalloproteinase-12 induces blood-brain barrier damage after focal cerebral ischemia. Stroke. 2015;46:3523–3531. doi: 10.1161/STROKEAHA.115.011031Zhao B.Q., Wang S., Kim H.Y., Storrie H., Rosen B.R., Mooney D.J., et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med. 2006;12(4):441–5. doi: 10.1038/nm1387Zhao B.Q., Wang S., Kim H.Y., Storrie H., Rosen B.R., Mooney D.J., et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med. 2006;12(4):441–5. doi: 10.1038/nm1387Sood R.R., Taheri S., Candelario-Jalil E., Estrada E.Y., Rosenberg G.A. Early benefi cial effect of matrix metalloproteinase inhibition on blood-brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain. J Cereb Blood Flow Metab. 2008;28(2):431–8. doi: 10.1038/sj.jcbfm.9600534Sood R.R., Taheri S., Candelario-Jalil E., Estrada E.Y., Rosenberg G.A. Early benefi cial effect of matrix metalloproteinase inhibition on blood-brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain. J Cereb Blood Flow Metab. 2008;28(2):431–8. doi: 10.1038/sj.jcbfm.9600534Wójcik-Stanaszek L., Sypecka J., Szymczak P., Ziemka-Nalecz M., Khrestchatisky M., Rivera S., Zalewska T. The potential role of metalloproteinases in neurogenesis in the gerbil hippocampus following global forebrain ischemia. PLoS One. 2011;6(7):e22465. doi: 10.1371/journal.pone.0022465Wójcik-Stanaszek L., Sypecka J., Szymczak P., Ziemka-Nalecz M., Khrestchatisky M., Rivera S., Zalewska T. The potential role of metalloproteinases in neurogenesis in the gerbil hippocampus following global forebrain ischemia. PLoS One. 2011;6(7):e22465. doi: 10.1371/journal.pone.0022465Wang L., Zhang Z.G., Zhang R.L., Gregg S.R., Hozeska-Solgot A., LeTourneau Y., Wang Y. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. Journal of Neuroscience. 2006;26(22):5996–6003. doi: 10.1523/JNEUROSCI.5380-05.2006Wang L., Zhang Z.G., Zhang R.L., Gregg S.R., Hozeska-Solgot A., LeTourneau Y., Wang Y. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. Journal of Neuroscience. 2006;26(22):5996–6003. doi: 10.1523/JNEUROSCI.5380-05.2006Ma F., Martínez-San Segundo P., Barceló V., Morancho A., Gabriel-Salazar M., Giralt D. et al. Matrix metalloproteinase-13 participates in neuroprotection and neurorepair after cerebral ischemia in mice. Neurobiol Dis. 2016;91:236–46. doi: 10.1016/j.nbd.2016.03.016Ma F., Martínez-San Segundo P., Barceló V., Morancho A., Gabriel-Salazar M., Giralt D. et al. Matrix metalloproteinase-13 participates in neuroprotection and neurorepair after cerebral ischemia in mice. Neurobiol Dis. 2016;91:236–46. doi: 10.1016/j.nbd.2016.03.016Ould-Yahoui A., Sbai O., Baranger K., Bernard A., Gueye Y., Charrat E. et al. Role of matrix metalloproteinases in migration and neurotrophic properties of nasal olfactory stem and ensheathing cells. Cell Transplant. 2013;22(6):993–1010. doi: 10.3727/096368912X657468Ould-Yahoui A., Sbai O., Baranger K., Bernard A., Gueye Y., Charrat E. et al. Role of matrix metalloproteinases in migration and neurotrophic properties of nasal olfactory stem and ensheathing cells. Cell Transplant. 2013;22(6):993–1010. doi: 10.3727/096368912X657468Esquiva G., Grayston A., Rosell A. Revascularization and endothelial progenitor cells in stroke. Am J Physiol Cell Physiol. 2018;315(5):664–674. doi: 10.1152/ajpcell.00200.2018Esquiva G., Grayston A., Rosell A. Revascularization and endothelial progenitor cells in stroke. Am J Physiol Cell Physiol. 2018;315(5):664–674. doi: 10.1152/ajpcell.00200.2018Huang P.H., Chen Y.H., Wang C.H., Chen J.S., Tsai H.Y., Lin F.Y. et al. Matrix metalloproteinase-9 is essential for ischemia-induced neovascularization by modulating bone marrow-derived endothelial progenitor cells. Arterioscler Thromb Vasc Biol. 2009;29(8):1179–84. doi: 10.1161/ATVBAHA.109.189175Huang P.H., Chen Y.H., Wang C.H., Chen J.S., Tsai H.Y., Lin F.Y. et al. Matrix metalloproteinase-9 is essential for ischemia-induced neovascularization by modulating bone marrow-derived endothelial progenitor cells. Arterioscler Thromb Vasc Biol. 2009;29(8):1179–84. doi: 10.1161/ATVBAHA.109.189175Morancho A., Hernández-Guillamon M., Boada C., Barceló V., Giralt D., Ortega L. et al. Cerebral ischaemia and matrix metalloproteinase-9 modulate the angiogenic function of early and late outgrowth endothelial progenitor cells. J Cell Mol Med. 2013;17(12):1543–53. doi: 10.1111/jcmm.12116Morancho A., Hernández-Guillamon M., Boada C., Barceló V., Giralt D., Ortega L. et al. Cerebral ischaemia and matrix metalloproteinase-9 modulate the angiogenic function of early and late outgrowth endothelial progenitor cells. J Cell Mol Med. 2013;17(12):1543–53. doi: 10.1111/jcmm.12116Liu C., Xie J., Sun S., Li H., Li T., Jiang C. et al. Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment in Acute Ischemic Stroke. Cell Mol Neurobiol. 2022;42(3):621–646. doi: 10.1007/s10571-020-00985-1Liu C., Xie J., Sun S., Li H., Li T., Jiang C. et al. Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment in Acute Ischemic Stroke. Cell Mol Neurobiol. 2022;42(3):621–646. doi: 10.1007/s10571-020-00985-1Wang L., Wei C., Deng L., Wang Z., Song M., Xiong Y. The accuracy of serum matrix metalloproteinase-9 for predicting hemorrhagic transformation after acute ischemic stroke : a systematic review and metaanalysis. J Stroke Cerebrovasc Dis. 2018;27(6):1653–65. doi: 10.1016/j.jstrokecerebrovasdis.2018.01.023Wang L., Wei C., Deng L., Wang Z., Song M., Xiong Y. The accuracy of serum matrix metalloproteinase-9 for predicting hemorrhagic transformation after acute ischemic stroke : a systematic review and metaanalysis. J Stroke Cerebrovasc Dis. 2018;27(6):1653–65. doi: 10.1016/j.jstrokecerebrovasdis.2018.01.023Miao Y., Liao J.K. Potential serum biomarkers in the pathophysiological processes of stroke. Expert Rev Neurother. 2014;14(2):173–85. doi: 10.1586/14737175.2014.875471.Miao Y., Liao J.K. Potential serum biomarkers in the pathophysiological processes of stroke. Expert Rev Neurother. 2014;14(2):173–85. doi: 10.1586/14737175.2014.875471.Sumii T., Lo E.H. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke. 2002;33(3):831–6. doi: 10.1161/hs0302.104542Sumii T., Lo E.H. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke. 2002;33(3):831–6. doi: 10.1161/hs0302.104542Mishiro K., Ishiguro M., Suzuki Y., Tsuruma K., Shimazawa M., Hara H. A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice. Neuroscience. 2012;205:39–48. doi: 10.1016/j.neuroscience.2011.12.042Mishiro K., Ishiguro M., Suzuki Y., Tsuruma K., Shimazawa M., Hara H. A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice. Neuroscience. 2012;205:39–48. doi: 10.1016/j.neuroscience.2011.12.042Fagan S.C., Waller J.L., Nichols F.T., Edwards D.J., Pettigrew L.C., Clark W.M. et al. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke. 2010;41(10):2283–7. doi: 10.1161/STROKEAHA.110.582601Fagan S.C., Waller J.L., Nichols F.T., Edwards D.J., Pettigrew L.C., Clark W.M. et al. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke. 2010;41(10):2283–7. doi: 10.1161/STROKEAHA.110.582601Switzer J.A., Hess D.C., Ergul A., Waller J.L., Machado L.S., Portik-Dobos V. et al. Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke. 2011;42(9):2633–5. doi: 10.1161/STROKEAHA.111.618215Switzer J.A., Hess D.C., Ergul A., Waller J.L., Machado L.S., Portik-Dobos V. et al. Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke. 2011;42(9):2633–5. doi: 10.1161/STROKEAHA.111.618215Ramos-Fernandez M., Bellolio M.F., Stead L.G. Matrix metalloproteinase-9 as a marker for acute ischemic stroke : a systematic review. J Stroke Cerebrovasc Dis. 2011;20(1):47–54. doi: 10.1016/j.jstrokecerebrovasdis.2009.10.008Ramos-Fernandez M., Bellolio M.F., Stead L.G. Matrix metalloproteinase-9 as a marker for acute ischemic stroke : a systematic review. J Stroke Cerebrovasc Dis. 2011;20(1):47–54. doi: 10.1016/j.jstrokecerebrovasdis.2009.10.008Castellanos M., Sobrino T., Millán M., García M., Arenillas J., Nombela F. Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: a multicenter confirmatory study. Stroke. 2007;38(6):1855–9. doi: 10.1161/STROKEAHA.106.481556Castellanos M., Sobrino T., Millán M., García M., Arenillas J., Nombela F. Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: a multicenter confirmatory study. Stroke. 2007;38(6):1855–9. doi: 10.1161/STROKEAHA.106.481556Tejima E., Guo S., Murata Y., Arai K., Lok J., van Leyen K. et al. Neuroprotective effects of overexpressing tissue inhibitor of metalloproteinase TIMP-1. J Neurotrauma. 2009;26(11):1935–41. doi: 10.1089/neu.2009.0959Tejima E., Guo S., Murata Y., Arai K., Lok J., van Leyen K. et al. Neuroprotective effects of overexpressing tissue inhibitor of metalloproteinase TIMP-1. J Neurotrauma. 2009;26(11):1935–41. doi: 10.1089/neu.2009.0959Jiang X., Namura S., Nagata I. Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neurosci Lett. 2001;305(1):41–4. doi: 10.1016/s0304-3940(01)01800-6Jiang X., Namura S., Nagata I. Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neurosci Lett. 2001;305(1):41–4. doi: 10.1016/s0304-3940(01)01800-6Romanic A.M., White R.F., Arleth A.J., Ohlstein E.H., Barone F.C. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke. 1998;29(5):1020–30. doi: 10.1161/01.str.29.5.1020.Romanic A.M., White R.F., Arleth A.J., Ohlstein E.H., Barone F.C. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke. 1998;29(5):1020–30. doi: 10.1161/01.str.29.5.1020.Manso H., Krug T., Sobral J. Variants of the Matrix Metalloproteinase-2 but not the Matrix Metalloproteinase-9 genes significantly infl uence functional outcome after stroke. BMC Med Genet. 2010;11(40). doi: 10.1186/1471-2350-11-40Manso H., Krug T., Sobral J. Variants of the Matrix Metalloproteinase-2 but not the Matrix Metalloproteinase-9 genes significantly infl uence functional outcome after stroke. BMC Med Genet. 2010;11(40). doi: 10.1186/1471-2350-11-40Cui J., Chen S., Zhang C., Meng F., Wu W., Hu R. et al. Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia. Mol Neurodegener. 2012;7:21. doi: 10.1186/1750-1326-7-21Cui J., Chen S., Zhang C., Meng F., Wu W., Hu R. et al. Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia. Mol Neurodegener. 2012;7:21. doi: 10.1186/1750-1326-7-21Ranasinghe H.S., Scheepens A., Sirimanne E., Mitchell M.D., Williams C.E., Fraser M. Inhibition of MMP-9 activity following hypoxic ischemia in the developing brain using a highly specific inhibitor. Dev Neurosci. 2012;34(5):417–27. doi: 10.1159/000343257Ranasinghe H.S., Scheepens A., Sirimanne E., Mitchell M.D., Williams C.E., Fraser M. Inhibition of MMP-9 activity following hypoxic ischemia in the developing brain using a highly specific inhibitor. Dev Neurosci. 2012;34(5):417–27. doi: 10.1159/000343257Machado L.S., Sazonova I.Y., Kozak A., Wiley D.C., El-Remessy A.B., Ergul A. et al. Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke. 2009;40(9):3028–33. doi: 10.1161/STROKEAHA.109.556852Machado L.S., Sazonova I.Y., Kozak A., Wiley D.C., El-Remessy A.B., Ergul A. et al. Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke. 2009;40(9):3028–33. doi: 10.1161/STROKEAHA.109.556852Machado L.S., Kozak A., Ergul A., Hess D.C., Borlongan C.V., Fagan S.C. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci. 2006;7:56. doi: 10.1186/1471-2202-7-56Machado L.S., Kozak A., Ergul A., Hess D.C., Borlongan C.V., Fagan S.C. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci. 2006;7:56. doi: 10.1186/1471-2202-7-56Zhang L., Chopp M., Jia L., Cui Y., Lu M., Zhang Z.G. Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats. J Cereb Blood Flow Metab. 2009;29(11):1816–24. doi: 10.1038/jcbfm.2009.105Zhang L., Chopp M., Jia L., Cui Y., Lu M., Zhang Z.G. Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats. J Cereb Blood Flow Metab. 2009;29(11):1816–24. doi: 10.1038/jcbfm.2009.105Jang J.W., Lee J.K., Lee M.C., Piao M.S., Kim S.H., Kim H.S. Melatonin reduced the elevated matrix metalloproteinase-9 level in a rat photothrombotic stroke model. J Neurol Sci. 2012;323(1–2):221–7. doi: 10.1016/j.jns.2012.09.021Jang J.W., Lee J.K., Lee M.C., Piao M.S., Kim S.H., Kim H.S. Melatonin reduced the elevated matrix metalloproteinase-9 level in a rat photothrombotic stroke model. J Neurol Sci. 2012;323(1–2):221–7. doi: 10.1016/j.jns.2012.09.021Tanaka H., Takai S., Jin D., Furubayashi K., Inoue N., Kajimoto Y. et al. Inhibition of matrix metalloproteinase-9 activity by trandolapril after middle cerebral artery occlusion in rats. Hypertens Res. 2007;30(5):469–75. doi: 10.1291/hypres.30.469Tanaka H., Takai S., Jin D., Furubayashi K., Inoue N., Kajimoto Y. et al. Inhibition of matrix metalloproteinase-9 activity by trandolapril after middle cerebral artery occlusion in rats. Hypertens Res. 2007;30(5):469–75. doi: 10.1291/hypres.30.469Candelario-Jalil E., Taheri S., Yang Y., Sood R., Grossetete M., Estrada E.Y. et al. Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. J Pharmacol Exp Ther. 2007;323(2):488–98. doi: 10.1124/jpet.107.127035Candelario-Jalil E., Taheri S., Yang Y., Sood R., Grossetete M., Estrada E.Y. et al. Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. J Pharmacol Exp Ther. 2007;323(2):488–98. doi: 10.1124/jpet.107.127035Hamann G.F., Burggraf D., Martens H.K., Liebetrau M., Jäger G., Wunderlich N. et al. Mild to moderate hypothermia prevents microvascular basal lamina antigen loss in experimental focal cerebral ischemia. Stroke. 2004;35(3):764–9. doi: 10.1161/01.STR.0000116866.60794.21Hamann G.F., Burggraf D., Martens H.K., Liebetrau M., Jäger G., Wunderlich N. et al. Mild to moderate hypothermia prevents microvascular basal lamina antigen loss in experimental focal cerebral ischemia. Stroke. 2004;35(3):764–9. doi: 10.1161/01.STR.0000116866.60794.21Rodríguez J.A., Sobrino T., Orbe J., Purroy A., Martínez-Vila E., Castillo J., Páramo J.A. proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke. J Thromb Haemost. 2013;11(8):1464–73. doi: 10.1111/jth.12312Rodríguez J.A., Sobrino T., Orbe J., Purroy A., Martínez-Vila E., Castillo J., Páramo J.A. proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke. J Thromb Haemost. 2013;11(8):1464–73. doi: 10.1111/jth.12312Horstmann S., Kalb P., Koziol J., Gardner H., Wagner S. Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke. 2003;34(9):2165–70. doi: 10.1161/01.STR.0000088062.86084.F2Horstmann S., Kalb P., Koziol J., Gardner H., Wagner S. Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke. 2003;34(9):2165–70. doi: 10.1161/01.STR.0000088062.86084.F2Worthmann H., Tryc A.B., Goldbecker A., Ma Y.T., Tountopoulou A., Hahn A., et al. The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis. 2010;30(1):85–92. doi: 10.1159/000314624Worthmann H., Tryc A.B., Goldbecker A., Ma Y.T., Tountopoulou A., Hahn A., et al. The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis. 2010;30(1):85–92. doi: 10.1159/000314624Tayebjee M.H., Nadar S., Blann A.D., Gareth Beevers D., Mac-Fadyen R.J., Lip G.Y. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Am J Hypertens. 2004;17(9):764–9. doi: 10.1016/j.amjhyper.2004.05.019Tayebjee M.H., Nadar S., Blann A.D., Gareth Beevers D., Mac-Fadyen R.J., Lip G.Y. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Am J Hypertens. 2004;17(9):764–9. doi: 10.1016/j.amjhyper.2004.05.019Eldrup N., Grønholdt M.L., Sillesen H., Nordestgaard B.G. Elevated matrix metalloproteinase-9 associated with stroke or cardiovascular death in patients with carotid stenosis. Circulation. 2006;114(17):1847–54. doi: 10.1161/CIRCULATIONAHA.105.593483Eldrup N., Grønholdt M.L., Sillesen H., Nordestgaard B.G. Elevated matrix metalloproteinase-9 associated with stroke or cardiovascular death in patients with carotid stenosis. Circulation. 2006;114(17):1847–54. doi: 10.1161/CIRCULATIONAHA.105.593483Zielinska-Turek J., Dorobek M., Turek G., Barcikowska-Kotowicz M. MMP-9 and/or TIMP as predictors of ischaemic stroke in patients with symptomatic and asymptomatic atherosclerotic stenosis of carotid artery treated by stenting or endarterectomy — A review. Neurol Neurochir Pol. 2018;52(5):555–561. doi: 10.1016/j.pjnns.2018.05.005Zielinska-Turek J., Dorobek M., Turek G., Barcikowska-Kotowicz M. MMP-9 and/or TIMP as predictors of ischaemic stroke in patients with symptomatic and asymptomatic atherosclerotic stenosis of carotid artery treated by stenting or endarterectomy — A review. Neurol Neurochir Pol. 2018;52(5):555–561. doi: 10.1016/j.pjnns.2018.05.005Peeters W., Moll F.L., Vink A., van der Spek P.J., de Kleijn D.P., de Vries J.P. et al. Collagenase matrix metalloproteinase-8 expressed in atherosclerotic carotid plaques is associated with systemic cardiovascular outcome. Eur Heart J. 2011;32(18):2314–25. doi: 10.1093/eurheartj/ehq517Peeters W., Moll F.L., Vink A., van der Spek P.J., de Kleijn D.P., de Vries J.P. et al. Collagenase matrix metalloproteinase-8 expressed in atherosclerotic carotid plaques is associated with systemic cardiovascular outcome. Eur Heart J. 2011;32(18):2314–25. doi: 10.1093/eurheartj/ehq517Tsioufi s C., Konstantinidis D., Nikolakopoulos I., Vemmou E., Kalos T., Georgiopoulos G. et al. Biomarkers of Atrial Fibrillation in Hypertension. Curr Med Chem. 2019;26(5):888–897. doi: 10.2174/0929867324666171006155516Tsioufi s C., Konstantinidis D., Nikolakopoulos I., Vemmou E., Kalos T., Georgiopoulos G. et al. Biomarkers of Atrial Fibrillation in Hypertension. Curr Med Chem. 2019;26(5):888–897. doi: 10.2174/0929867324666171006155516Hijazi Z., Wallentin L., Lindbäck J., Alexander J.H., Connolly S.J., Eikelboom J.W. Screening of multiple biomarkers associated with ischemic stroke in atrial fi brillation. J Am Heart Assoc. 2020;9(24):e018984. doi: 10.1161/JAHA.120.018984Hijazi Z., Wallentin L., Lindbäck J., Alexander J.H., Connolly S.J., Eikelboom J.W. Screening of multiple biomarkers associated with ischemic stroke in atrial fi brillation. J Am Heart Assoc. 2020;9(24):e018984. doi: 10.1161/JAHA.120.018984Zhong C., Yang J., Xu T., Xu T., Peng Y., Wang A. et al. Serum matrix metalloproteinase-9 levels and prognosis of acute ischemic stroke. Neurology. 2017;89(8):805–812. doi: 10.1212/WNL.0000000000004257Zhong C., Yang J., Xu T., Xu T., Peng Y., Wang A. et al. Serum matrix metalloproteinase-9 levels and prognosis of acute ischemic stroke. Neurology. 2017;89(8):805–812. doi: 10.1212/WNL.0000000000004257

The authors declare that there are no conflicts of interest present.