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How arterial stiffness and sex interact at a molecular level to confer risk of CVD is not well understood. Here, we used the sexual dimorphism in LDLR-null mice to show that the protective effect of female sex on atherosclerosis is linked to reduced aortic stiffness and reduced expression of matrix metalloproteinase-12 (MMP12) by lesional macrophages. Deletion of MMP12 in LDLR-null mice attenuated the male sex bias for both arterial stiffness and atherosclerosis, and these effects occurred despite high serum cholesterol. Mechanistically, we found that oxidized LDL stimulates secretion of MMP12 in human as well as mouse macrophages. Estrogen antagonizes this effect by downregulating MMP12 expression. Our data support cholesterol-independent causal relationships between estrogen, oxidized LDL\u2013induced secretion of macrophage MMP12, and arterial stiffness that protect against atherosclerosis in females and emphasize that reduced MMP12 functionality can confer atheroprotection to males.<\/jats:p>","DOI":"10.1172\/jci.insight.122742","type":"journal-article","created":{"date-parts":[[2019,1,10]],"date-time":"2019-01-10T09:16:22Z","timestamp":1547111782000},"source":"Crossref","is-referenced-by-count":56,"title":["Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12"],"prefix":"10.1172","volume":"4","author":[{"given":"Shu-lin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anamika","family":"Bajpai","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Hawthorne","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."},{"name":"Center for Engineering MechanoBiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1838-1652","authenticated-orcid":true,"given":"Yongho","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Castagnino","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."},{"name":"Center for Engineering MechanoBiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Monslow","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-3711","authenticated-orcid":true,"given":"Ellen","family":"Pur\u00e9","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara L.","family":"Spiller","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard K.","family":"Assoian","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA."},{"name":"Center for Engineering MechanoBiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,1,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201412052"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306256"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306301"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2596"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt101"},{"key":"B6","doi-asserted-by":"crossref","DOI":"10.4061\/2011\/263585","article-title":"Vascular stiffness and increased pulse pressure in the aging cardiovascular system","volume":"2011","author":"Steppan","year":"2011","journal-title":"Cardiol Res Pract"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-5922.2008.00051.x"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-007-0010-y"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.886655"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.09.018"},{"issue":"112","key":"B11","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3002761","article-title":"Age-related intimal stiffening enhances endothelial permeability and leukocyte transmigration","volume":"3","author":"Huynh","year":"2011","journal-title":"Sci Transl Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00041.2008"},{"issue":"5","key":"B13","first-page":"585","article-title":"The aortic tunica media of the developing rat. 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