{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T21:53:19Z","timestamp":1793137999744,"version":"4.5.0"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/18\/1\/33234 and FS\/17\/60\/33474"],"award-info":[{"award-number":["FS\/18\/1\/33234 and FS\/17\/60\/33474"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/18\/1\/33234 and FS\/17\/60\/33474"],"award-info":[{"award-number":["FS\/18\/1\/33234 and FS\/17\/60\/33474"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP\/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.<\/jats:p>","DOI":"10.1038\/s41598-021-02508-4","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T12:53:32Z","timestamp":1638276812000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Disparate effects of MMP and TIMP modulation on coronary atherosclerosis and associated myocardial fibrosis"],"prefix":"10.1038","volume":"11","author":[{"given":"Georgios","family":"Kremastiotis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishita","family":"Handa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"George","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0630-9183","authenticated-orcid":false,"given":"Jason","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,30]]},"reference":[{"key":"2508_CR1","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1161\/CIRCRESAHA.114.302533","volume":"114","author":"M Rienks","year":"2014","unstructured":"Rienks, M., Papageorgiou, A. P., Frangogiannis, N. G. & Heymans, S. Myocardial extracellular matrix: an ever-changing and diverse entity. Circ. Res. 114, 872\u2013888. https:\/\/doi.org\/10.1161\/CIRCRESAHA.114.302533 (2014).","journal-title":"Circ. Res."},{"key":"2508_CR2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.bcp.2014.04.011","volume":"90","author":"FG Spinale","year":"2014","unstructured":"Spinale, F. G. & Villarreal, F. Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. Biochem. Pharmacol. 90, 7\u201315. https:\/\/doi.org\/10.1016\/j.bcp.2014.04.011 (2014).","journal-title":"Biochem. Pharmacol."},{"key":"2508_CR3","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.tem.2012.10.008","volume":"24","author":"O Soehnlein","year":"2013","unstructured":"Soehnlein, O. & Swirski, F. K. Hypercholesterolemia links hematopoiesis with atherosclerosis. Trends. Endocrinol. Metab. 24, 129\u2013136. https:\/\/doi.org\/10.1016\/j.tem.2012.10.008 (2013).","journal-title":"Trends. Endocrinol. Metab."},{"key":"2508_CR4","doi-asserted-by":"publisher","first-page":"1852","DOI":"10.1161\/CIRCRESAHA.114.302721","volume":"114","author":"JF Bentzon","year":"2014","unstructured":"Bentzon, J. F., Otsuka, F., Virmani, R. & Falk, E. Mechanisms of plaque formation and rupture. Circ. Res. 114, 1852\u20131866. https:\/\/doi.org\/10.1161\/CIRCRESAHA.114.302721 (2014).","journal-title":"Circ. Res."},{"key":"2508_CR5","doi-asserted-by":"publisher","first-page":"15575","DOI":"10.1073\/pnas.0506201102","volume":"102","author":"JL Johnson","year":"2005","unstructured":"Johnson, J. L., George, S. J., Newby, A. C. & Jackson, C. L. Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries. Proc. Natl. Acad. Sci. U S A 102, 15575\u201315580. https:\/\/doi.org\/10.1073\/pnas.0506201102 (2005).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"2508_CR6","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/276457","volume":"2014","author":"JL Johnson","year":"2014","unstructured":"Johnson, J. L. et al. Relationship of MMP-14 and TIMP-3 expression with macrophage activation and human atherosclerotic plaque vulnerability. Med. Inflamm. 2014, 276457. https:\/\/doi.org\/10.1155\/2014\/276457 (2014).","journal-title":"Med. Inflamm."},{"key":"2508_CR7","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1136\/heartjnl-2012-301623","volume":"98","author":"AM van der Laan","year":"2012","unstructured":"van der Laan, A. M., Nahrendorf, M. & Piek, J. J. Healing and adverse remodelling after acute myocardial infarction: role of the cellular immune response. Heart 98, 1384\u20131390. https:\/\/doi.org\/10.1136\/heartjnl-2012-301623 (2012).","journal-title":"Heart"},{"key":"2508_CR8","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1093\/cvr\/cvs109","volume":"94","author":"D Fraccarollo","year":"2012","unstructured":"Fraccarollo, D., Galuppo, P. & Bauersachs, J. Novel therapeutic approaches to post-infarction remodelling. Cardiovasc. Res. 94, 293\u2013303. https:\/\/doi.org\/10.1093\/cvr\/cvs109 (2012).","journal-title":"Cardiovasc. Res."},{"key":"2508_CR9","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/nrcardio.2014.28","volume":"11","author":"NG Frangogiannis","year":"2014","unstructured":"Frangogiannis, N. G. The inflammatory response in myocardial injury, repair, and remodelling. Nat. Rev. Cardiol. 11, 255\u2013265. https:\/\/doi.org\/10.1038\/nrcardio.2014.28 (2014).","journal-title":"Nat. Rev. Cardiol."},{"key":"2508_CR10","doi-asserted-by":"publisher","first-page":"H706","DOI":"10.1152\/ajpheart.00679.2019","volume":"318","author":"AR Kaminski","year":"2020","unstructured":"Kaminski, A. R. et al. The compendium of matrix metalloproteinase expression in the left ventricle of mice following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 318, H706\u2013H714. https:\/\/doi.org\/10.1152\/ajpheart.00679.2019 (2020).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2508_CR11","doi-asserted-by":"publisher","first-page":"2057","DOI":"10.1161\/CIRCULATIONAHA.108.784215","volume":"118","author":"RS Velagaleti","year":"2008","unstructured":"Velagaleti, R. S. et al. Long-term trends in the incidence of heart failure after myocardial infarction. Circulation 118, 2057\u20132062. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.108.784215 (2008).","journal-title":"Circulation"},{"key":"2508_CR12","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1093\/cvr\/cvv268","volume":"109","author":"K Di Gregoli","year":"2016","unstructured":"Di Gregoli, K., George, S. J., Jackson, C. L., Newby, A. C. & Johnson, J. L. Differential effects of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 on atherosclerosis and monocyte\/macrophage invasion. Cardiovasc. Res. 109, 318\u2013330. https:\/\/doi.org\/10.1093\/cvr\/cvv268 (2016).","journal-title":"Cardiovasc. Res."},{"key":"2508_CR13","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1161\/CIRCULATIONAHA.106.613281","volume":"113","author":"JL Johnson","year":"2006","unstructured":"Johnson, J. L. et al. Suppression of atherosclerotic plaque progression and instability by tissue inhibitor of metalloproteinase-2: involvement of macrophage migration and apoptosis. Circulation 113, 2435\u20132444. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.106.613281 (2006).","journal-title":"Circulation"},{"key":"2508_CR14","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/0092-8674(92)90362-g","volume":"71","author":"AS Plump","year":"1992","unstructured":"Plump, A. S. et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71, 343\u2013353. https:\/\/doi.org\/10.1016\/0092-8674(92)90362-g (1992).","journal-title":"Cell"},{"key":"2508_CR15","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1126\/science.1411543","volume":"258","author":"SH Zhang","year":"1992","unstructured":"Zhang, S. H., Reddick, R. L., Piedrahita, J. A. & Maeda, N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258, 468\u2013471. https:\/\/doi.org\/10.1126\/science.1411543 (1992).","journal-title":"Science"},{"key":"2508_CR16","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1073\/pnas.94.4.1402","volume":"94","author":"CL Wilson","year":"1997","unstructured":"Wilson, C. L., Heppner, K. J., Labosky, P. A., Hogan, B. L. M. & Matrisian, L. M. Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc. Natl. Acad. Sci. 94, 1402\u20131407 (1997).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"2508_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)81169-1","author":"TH Vu","year":"1998","unstructured":"Vu, T. H. et al. MMP-9\/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell https:\/\/doi.org\/10.1016\/s0092-8674(00)81169-1 (1998).","journal-title":"Cell"},{"key":"2508_CR18","doi-asserted-by":"publisher","first-page":"3942","DOI":"10.1073\/pnas.93.9.3942","volume":"93","author":"JM Shipley","year":"1996","unstructured":"Shipley, J. M., Wesselschmidt, R. L., Kobayashi, D. K., Ley, T. J. & Shapiro, S. D. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Natl. Acad. Sci. USA 93, 3942\u20133946 (1996).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2508_CR19","first-page":"2307","volume":"13","author":"P Soloway","year":"1996","unstructured":"Soloway, P., Alexander, C. M., Werb, Z. & Jaenisch, R. Targeted mutagenesis of TIMP-1 reveals that lung tumour invasion is influenced by TIMP-1 genotype of the tumour but not by that of the host. Oncogene 13, 2307\u20132314 (1996).","journal-title":"Oncogene"},{"key":"2508_CR20","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1016\/j.cardiores.2006.05.009","volume":"71","author":"JL Johnson","year":"2006","unstructured":"Johnson, J. L. et al. Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability. Cardiovasc. Res. 71, 586\u2013595. https:\/\/doi.org\/10.1016\/j.cardiores.2006.05.009 (2006).","journal-title":"Cardiovasc. Res."},{"key":"2508_CR21","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/S0021-9150(00)00515-3","volume":"154","author":"JL Johnson","year":"2001","unstructured":"Johnson, J. L. & Jackson, C. L. Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse. Atherosclerosis 154, 399\u2013406 (2001).","journal-title":"Atherosclerosis"},{"key":"2508_CR22","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1161\/01.ATV.0000014587.66321.B4","volume":"22","author":"H Williams","year":"2002","unstructured":"Williams, H., Johnson, J. L., Carson, K. G. S. & Jackson, C. L. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 22, 788\u2013792 (2002).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2508_CR23","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1161\/01.CIR.0000158435.98035.8D","volume":"111","author":"J Johnson","year":"2005","unstructured":"Johnson, J. et al. Plaque rupture after short periods of fat-feeding in the apolipoprotein E knockout mouse: model characterisation, and effects of pravastatin treatment. Circulation 111, 1422\u20131430 (2005).","journal-title":"Circulation"},{"key":"2508_CR24","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.ejphar.2017.09.007","volume":"816","author":"JL Johnson","year":"2017","unstructured":"Johnson, J. L. Metalloproteinases in atherosclerosis. Eur. J. Pharmacol. 816, 93\u2013106. https:\/\/doi.org\/10.1016\/j.ejphar.2017.09.007 (2017).","journal-title":"Eur. J. Pharmacol."},{"key":"2508_CR25","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/bs.pmbts.2017.02.001","volume":"147","author":"KY DeLeon-Pennell","year":"2017","unstructured":"DeLeon-Pennell, K. Y., Meschiari, C. A., Jung, M. & Lindsey, M. L. Matrix metalloproteinases in myocardial infarction and heart failure. Prog. Mol. Biol. Transl. Sci. 147, 75\u2013100. https:\/\/doi.org\/10.1016\/bs.pmbts.2017.02.001 (2017).","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"2508_CR26","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1161\/01.cir.0000091087.78630.79","volume":"108","author":"WM Yarbrough","year":"2003","unstructured":"Yarbrough, W. M. et al. Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling. Circulation 108, 1753\u20131759. https:\/\/doi.org\/10.1161\/01.cir.0000091087.78630.79 (2003).","journal-title":"Circulation"},{"key":"2508_CR27","doi-asserted-by":"publisher","first-page":"9748","DOI":"10.1073\/pnas.93.18.9748","volume":"93","author":"I Halpert","year":"1996","unstructured":"Halpert, I. et al. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc. Natl. Acad. Sci. USA 93, 9748\u20139753 (1996).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2508_CR28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084935","volume":"9","author":"A Abbas","year":"2014","unstructured":"Abbas, A. et al. Matrix metalloproteinase 7 is associated with symptomatic lesions and adverse events in patients with carotid atherosclerosis. PLoS ONE 9, e84935. https:\/\/doi.org\/10.1371\/journal.pone.0084935 (2014).","journal-title":"PLoS ONE"},{"key":"2508_CR29","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1093\/cvr\/cvq042","volume":"87","author":"H Williams","year":"2010","unstructured":"Williams, H., Johnson, J. L., Jackson, C. L., White, S. J. & George, S. J. MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis. Cardiovasc. Res. 87, 137\u2013146. https:\/\/doi.org\/10.1093\/cvr\/cvq042 (2010).","journal-title":"Cardiovasc. Res."},{"key":"2508_CR30","doi-asserted-by":"publisher","first-page":"2919","DOI":"10.1161\/circulationaha.106.612960","volume":"113","author":"ML Lindsey","year":"2006","unstructured":"Lindsey, M. L. et al. Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. Circulation 113, 2919\u20132928. https:\/\/doi.org\/10.1161\/circulationaha.106.612960 (2006).","journal-title":"Circulation"},{"key":"2508_CR31","doi-asserted-by":"publisher","first-page":"6292","DOI":"10.1073\/pnas.092134099","volume":"99","author":"F Zuo","year":"2002","unstructured":"Zuo, F. et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc. Natl. Acad. Sci. U S A 99, 6292\u20136297. https:\/\/doi.org\/10.1073\/pnas.092134099 (2002).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"2508_CR32","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1038\/modpathol.3800374","volume":"18","author":"CC Huang","year":"2005","unstructured":"Huang, C. C. et al. Matrilysin (MMP-7) is a major matrix metalloproteinase upregulated in biliary atresia-associated liver fibrosis. Mod. Pathol. 18, 941\u2013950. https:\/\/doi.org\/10.1038\/modpathol.3800374 (2005).","journal-title":"Mod. Pathol."},{"key":"2508_CR33","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/s0168-8278(00)00037-4","volume":"34","author":"R Lichtinghagen","year":"2001","unstructured":"Lichtinghagen, R. et al. Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C. J. Hepatol. 34, 239\u2013247. https:\/\/doi.org\/10.1016\/s0168-8278(00)00037-4 (2001).","journal-title":"J. Hepatol."},{"key":"2508_CR34","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1007\/s00395-020-0789-z","volume":"115","author":"Y Yang","year":"2020","unstructured":"Yang, Y. et al. Matrix metalloproteinase-7 in platelet-activated macrophages accounts for cardiac remodeling in uremic mice. Basic Res. Cardiol. 115, 30. https:\/\/doi.org\/10.1007\/s00395-020-0789-z (2020).","journal-title":"Basic Res. Cardiol."},{"key":"2508_CR35","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1161\/01.CIR.0000121728.14930.DE","volume":"109","author":"A Luttun","year":"2004","unstructured":"Luttun, A. et al. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation 109, 1408\u20131414 (2004).","journal-title":"Circulation"},{"key":"2508_CR36","doi-asserted-by":"publisher","first-page":"e35","DOI":"10.1161\/ATVBAHA.111.225623","volume":"31","author":"JL Johnson","year":"2011","unstructured":"Johnson, J. L., Dwivedi, A., Somerville, M., George, S. J. & Newby, A. C. Matrix metalloproteinase (MMP)-3 activates MMP-9 mediated vascular smooth muscle cell migration and neointima formation in mice. Arterioscler Thromb. Vasc. Biol. 31, e35-44. https:\/\/doi.org\/10.1161\/ATVBAHA.111.225623 (2011).","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"2508_CR37","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1161\/01.RES.0000040420.17366.2E","volume":"91","author":"A Cho","year":"2002","unstructured":"Cho, A. & Reidy, M. A. Matrix metalloproteinase-9 is necessary for the regulation of smooth muscle cell replication and migration after arterial injury. Circ. Res. 91, 845\u2013851 (2002).","journal-title":"Circ. Res."},{"key":"2508_CR38","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1161\/01.ATV.0000161275.82687.f6","volume":"25","author":"ET Choi","year":"2005","unstructured":"Choi, E. T. et al. Matrix metalloproteinase-9 modulation by resident arterial cells is responsible for injury-induced accelerated atherosclerotic plaque development in apolipoprotein E-deficient mice. Arterioscler Thromb. Vasc. Biol. 25, 1020\u20131025 (2005).","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"2508_CR39","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1161\/01.ATV.0000100402.69997.C3","volume":"24","author":"C Johnson","year":"2004","unstructured":"Johnson, C. & Galis, Z. S. Matrix metalloproteinase-2 and-9 differentially regulate smooth muscle cell migration and cell-mediated collagen organization. Arterioscler Thromb. Vasc. Biol. 24, 54\u201360 (2004).","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"2508_CR40","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.yjmcc.2014.04.007","volume":"72","author":"TA Ramirez","year":"2014","unstructured":"Ramirez, T. A. et al. Aliskiren and valsartan mediate left ventricular remodeling post-myocardial infarction in mice through MMP-9 effects. J. Mol. Cell. Cardiol. 72, 326\u2013335. https:\/\/doi.org\/10.1016\/j.yjmcc.2014.04.007 (2014).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2508_CR41","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.yjmcc.2012.07.017","volume":"53","author":"R Zamilpa","year":"2012","unstructured":"Zamilpa, R. et al. Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and improves left ventricular function post-myocardial infarction. J. Mol. Cell. Cardiol. 53, 599\u2013608. https:\/\/doi.org\/10.1016\/j.yjmcc.2012.07.017 (2012).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2508_CR42","doi-asserted-by":"publisher","first-page":"H190","DOI":"10.1152\/ajpheart.00243.2016","volume":"311","author":"RP Iyer","year":"2016","unstructured":"Iyer, R. P., Jung, M. & Lindsey, M. L. MMP-9 signaling in the left ventricle following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 311, H190-198. https:\/\/doi.org\/10.1152\/ajpheart.00243.2016 (2016).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2508_CR43","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1172\/JCI8768","volume":"106","author":"A Ducharme","year":"2000","unstructured":"Ducharme, A. et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J. Clin. Invest. 106, 55\u201362 (2000).","journal-title":"J. Clin. Invest."},{"key":"2508_CR44","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.008024","author":"X Wang","year":"2018","unstructured":"Wang, X., Guo, Z., Ding, Z. & Mehta, J. L. Inflammation, autophagy, and apoptosis after myocardial infarction. J. Am. Heart Assoc. https:\/\/doi.org\/10.1161\/JAHA.117.008024 (2018).","journal-title":"J. Am. Heart Assoc."},{"key":"2508_CR45","doi-asserted-by":"publisher","first-page":"H1414","DOI":"10.1152\/ajpheart.00032.2020","volume":"319","author":"SS Nandi","year":"2020","unstructured":"Nandi, S. S. et al. MMP9 inhibition increases autophagic flux in chronic heart failure. Am. J. Physiol. Heart Circ. Physiol. 319, H1414-h1437. https:\/\/doi.org\/10.1152\/ajpheart.00032.2020 (2020).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2508_CR46","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.2353\/ajpath.2008.070604","volume":"172","author":"S Yamada","year":"2008","unstructured":"Yamada, S. et al. Matrix metalloproteinase 12 accelerates the initiation of atherosclerosis and stimulates the progression of fatty streaks to fibrous plaques in transgenic rabbits. Am. J. Pathol. 172, 1419\u20131429. https:\/\/doi.org\/10.2353\/ajpath.2008.070604 (2008).","journal-title":"Am. J. Pathol."},{"key":"2508_CR47","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1161\/CIRCULATIONAHA.105.596031","volume":"113","author":"J Liang","year":"2006","unstructured":"Liang, J. et al. Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits. Circulation 113, 1993\u20132001 (2006).","journal-title":"Circulation"},{"key":"2508_CR48","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1161\/atvbaha.110.219147","volume":"31","author":"JL Johnson","year":"2011","unstructured":"Johnson, J. L. et al. A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein E-knockout mice. Arterioscler Thromb. Vasc. Biol. 31, 528\u2013535. https:\/\/doi.org\/10.1161\/atvbaha.110.219147 (2011).","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"2508_CR49","doi-asserted-by":"publisher","DOI":"10.1161\/jaha.112.001040","volume":"1","author":"VPW Scholtes","year":"2012","unstructured":"Scholtes, V. P. W. et al. Carotid atherosclerotic plaque matrix metalloproteinase-12\u2013positive macrophage subpopulation predicts adverse outcome after endarterectomy. JAHA 1, e001040. https:\/\/doi.org\/10.1161\/jaha.112.001040 (2012).","journal-title":"JAHA"},{"key":"2508_CR50","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.ijcard.2015.03.054","volume":"185","author":"RP Iyer","year":"2015","unstructured":"Iyer, R. P. et al. Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution. Int. J. Cardiol. 185, 198\u2013208. https:\/\/doi.org\/10.1016\/j.ijcard.2015.03.054 (2015).","journal-title":"Int. J. Cardiol."},{"key":"2508_CR51","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.yjmcc.2019.04.007","volume":"131","author":"A Kubota","year":"2019","unstructured":"Kubota, A., Suto, A., Suzuki, K., Kobayashi, Y. & Nakajima, H. Matrix metalloproteinase-12 produced by Ly6C low macrophages prolongs the survival after myocardial infarction by preventing neutrophil influx. J. Mol. Cell. Cardiol. 131, 41\u201352. https:\/\/doi.org\/10.1016\/j.yjmcc.2019.04.007 (2019).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2508_CR52","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1172\/JCI29950","volume":"117","author":"FK Swirski","year":"2007","unstructured":"Swirski, F. K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195\u2013205 (2007).","journal-title":"J. Clin. Invest."},{"key":"2508_CR53","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1161\/01.RES.0000016501.56641.83","volume":"90","author":"J Silence","year":"2002","unstructured":"Silence, J., Collen, D. & Lijnen, H. R. Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene. Circ. Res. 90, 897\u2013903 (2002).","journal-title":"Circ. Res."},{"key":"2508_CR54","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1161\/01.CIR.100.5.533","volume":"100","author":"M Rouis","year":"1999","unstructured":"Rouis, M. et al. Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E-deficient mice. Circulation 100, 533\u2013540 (1999).","journal-title":"Circulation"},{"key":"2508_CR55","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1159\/000095309","volume":"43","author":"C Cuaz-Perolin","year":"2006","unstructured":"Cuaz-Perolin, C. et al. Apolipoprotein E knockout mice over-expressing human tissue inhibitor of metalloproteinase 1 are protected against aneurysm formation but not against atherosclerotic plaque development. J. Vasc. Res. 43, 493\u2013501 (2006).","journal-title":"J. Vasc. Res."},{"key":"2508_CR56","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1161\/01.CIR.0000044915.37074.5C","volume":"107","author":"V Lema\u00eetre","year":"2003","unstructured":"Lema\u00eetre, V., Soloway, P. D. & D\u2019Armiento, J. Increased medial degradation with pseudo-aneurysm formation in apolipoprotein E-knockout mice deficient in tissue inhibitor of metalloproteinases-1. Circulation 107, 333\u2013338 (2003).","journal-title":"Circulation"},{"key":"2508_CR57","doi-asserted-by":"publisher","first-page":"H149","DOI":"10.1152\/ajpheart.00370.2004","volume":"288","author":"JS Ikonomidis","year":"2005","unstructured":"Ikonomidis, J. S. et al. Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition. Am. J. Physiol. Heart Circ. Physiol. 288, H149\u2013H158. https:\/\/doi.org\/10.1152\/ajpheart.00370.2004 (2005).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2508_CR58","doi-asserted-by":"publisher","DOI":"10.3390\/jcm7110427","author":"CK Wu","year":"2018","unstructured":"Wu, C. K., Su, M. M., Wu, Y. F., Hwang, J. J. & Lin, L. Y. Combination of plasma biomarkers and clinical data for the detection of myocardial fibrosis or aggravation of heart failure symptoms in heart failure with preserved ejection fraction patients. J. Clin. Med. https:\/\/doi.org\/10.3390\/jcm7110427 (2018).","journal-title":"J. Clin. Med."},{"key":"2508_CR59","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1161\/CIRCULATIONAHA.104.516963","volume":"112","author":"S Heymans","year":"2005","unstructured":"Heymans, S. et al. Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation 112, 1136\u20131144. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.104.516963 (2005).","journal-title":"Circulation"},{"key":"2508_CR60","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/s10456-008-9102-8","volume":"11","author":"H Liu","year":"2008","unstructured":"Liu, H., Chen, B. & Lilly, B. Fibroblasts potentiate blood vessel formation partially through secreted factor TIMP-1. Angiogenesis 11, 223\u2013234. https:\/\/doi.org\/10.1007\/s10456-008-9102-8 (2008).","journal-title":"Angiogenesis"},{"key":"2508_CR61","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/s0026-2862(02)00026-2","volume":"65","author":"MJ Reed","year":"2003","unstructured":"Reed, M. J., Koike, T., Sadoun, E., Sage, E. H. & Puolakkainen, P. Inhibition of TIMP1 enhances angiogenesis in vivo and cell migration in vitro. Microvasc. Res. 65, 9\u201317. https:\/\/doi.org\/10.1016\/s0026-2862(02)00026-2 (2003).","journal-title":"Microvasc. Res."},{"key":"2508_CR62","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1161\/circresaha.109.209189","volume":"106","author":"V Kandalam","year":"2010","unstructured":"Kandalam, V. et al. TIMP2 deficiency accelerates adverse post-myocardial infarction remodeling because of enhanced MT1-MMP activity despite lack of MMP2 activation. Circ. Res. 106, 796\u2013808. https:\/\/doi.org\/10.1161\/circresaha.109.209189 (2010).","journal-title":"Circ. Res."},{"key":"2508_CR63","doi-asserted-by":"publisher","first-page":"H208","DOI":"10.1152\/ajpheart.00234.2021","volume":"321","author":"ML Lindsey","year":"2021","unstructured":"Lindsey, M. L. et al. Reperfused vs. nonreperfused myocardial infarction: when to use which model. Am. J. Physiol. Heart Circ. Physiol. 321, H208\u2013H213. https:\/\/doi.org\/10.1152\/ajpheart.00234.2021 (2021).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02508-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02508-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02508-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T12:44:16Z","timestamp":1670071456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-02508-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,30]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["2508"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-02508-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,30]]},"assertion":[{"value":"13 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"23081"}}