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Fujian","award":["2021J01383"],"award-info":[{"award-number":["2021J01383"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Aortic dissection (AD) is a lethal aortic pathology without effective medical treatments since the underlying pathological mechanisms responsible for AD remain elusive. Matrix metalloproteinase-8 (MMP8) has been previously identified as a key player in atherosclerosis and arterial remodeling. However, the functional role of MMP8 in AD remains largely unknown. Here, we report that an increased level of MMP8 was observed in 3-aminopropionitrile fumarate (BAPN)-induced murine AD. AD incidence and aortic elastin fragmentation were markedly reduced in MMP8-knockout mice. Importantly, pharmacologic inhibition of MMP8 significantly reduced the AD incidence and aortic elastin fragmentation. We observed less inflammatory cell accumulation, a lower level of aortic inflammation, and decreased smooth muscle cell (SMC) apoptosis in MMP8-knockout mice. In line with our previous observation that MMP8 cleaves Ang I to generate Ang II, BAPN-treated MMP8-knockout mice had increased levels of Ang I, but decreased levels of Ang II and lower blood pressure. Additionally, we observed a decreased expression level of vascular cell adhesion molecule-1 (VCAM1) and a reduced level of reactive oxygen species (ROS) in MMP8-knockout aortas. Mechanistically, our data show that the Ang II\/VCAM1 signal axis is responsible for MMP8-mediated inflammatory cell invasion and transendothelial migration, while MMP8-mediated SMC inflammation and apoptosis are attributed to Ang II\/ROS signaling. Finally, we observed higher levels of aortic and serum MMP8 in patients with AD. We therefore provide new insights into the molecular mechanisms underlying AD and identify MMP8 as a potential therapeutic target for this life-threatening aortic disease.<\/jats:p>","DOI":"10.3390\/cells11203218","type":"journal-article","created":{"date-parts":[[2022,10,16]],"date-time":"2022-10-16T21:10:10Z","timestamp":1665954610000},"page":"3218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Targeted Inhibition of Matrix Metalloproteinase-8 Prevents Aortic Dissection in a Murine Model"],"prefix":"10.3390","volume":"11","author":[{"given":"Chengxin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery, First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei 230022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3218-0694","authenticated-orcid":false,"given":"Kaiyuan","family":"Niu","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"},{"name":"Department of Otolaryngology, The Third Affiliated Hospital of Anhui Medical University, Huaihe Road, Luyang District, Hefei 230061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meixia","family":"Ren","sequence":"additional","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou 350005, China"},{"name":"Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for Geriatrics, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmiao","family":"Zhou","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3691-2103","authenticated-orcid":false,"given":"Zhisheng","family":"Yang","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Yang","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, 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Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Basic Medical College, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenglin","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei 230022, 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1001\/jama.2016.10026","article-title":"Acute Aortic Dissection and Intramural Hematoma: A Systematic Review","volume":"316","author":"Mussa","year":"2016","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/S0140-6736(14)61005-9","article-title":"Management of acute aortic dissection","volume":"385","author":"Nienaber","year":"2015","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1001\/jama.283.7.897","article-title":"The International Registry of Acute Aortic Dissection (IRAD): New insights into an old 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