{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:22:02Z","timestamp":1792678922520,"version":"4.5.0"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2016,5,6]]},"abstract":"\n Background<\/jats:title>\n \n Ascending thoracic aortic aneurysm (\n ATAA<\/jats:styled-content>\n ) is driven by angiotensin\n II<\/jats:styled-content>\n (Ang\n II<\/jats:styled-content>\n ) and contributes to the development of left ventricular (\n LV<\/jats:styled-content>\n ) remodeling through aortoventricular coupling. We previously showed that locally available leptin augments Ang\n II<\/jats:styled-content>\n \u2010induced abdominal aortic aneurysms in apolipoprotein E\u2013deficient mice. We hypothesized that locally synthesized leptin mediates Ang\n II<\/jats:styled-content>\n \u2010induced\n ATAA<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Following demonstration of leptin synthesis in samples of human\n ATAA<\/jats:styled-content>\n associated with different etiologies, we modeled in\u00a0situ leptin expression in apolipoprotein E\u2013deficient mice by applying exogenous leptin on the surface of the ascending aorta. This treatment resulted in local aortic stiffening and dilation,\n LV<\/jats:styled-content>\n hypertrophy, and thickening of aortic\/mitral valve leaflets. Similar results were obtained in an Ang\n II<\/jats:styled-content>\n \u2010infusion\n ATAA<\/jats:styled-content>\n mouse model. To test the dependence of Ang\n II<\/jats:styled-content>\n \u2010induced aortic and\n LV<\/jats:styled-content>\n remodeling on leptin activity, a leptin antagonist was applied to the ascending aorta in Ang\n II<\/jats:styled-content>\n \u2010infused mice. Locally applied single low\u2010dose leptin antagonist moderated Ang\n II<\/jats:styled-content>\n \u2010induced ascending aortic dilation and protected mice from\n ATAA<\/jats:styled-content>\n rupture. Furthermore,\n LV<\/jats:styled-content>\n hypertrophy was attenuated and thickening of aortic valve leaflets was moderated. Last, analysis of human aortic valve stenosis leaflets revealed de novo leptin synthesis, whereas exogenous leptin stimulated proliferation and promoted mineralization of human valve interstitial cells in culture.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Ang\n II<\/jats:styled-content>\n \u2010induced\n ATAA<\/jats:styled-content>\n is mediated by locally synthesized leptin. Aortoventricular hemodynamic coupling drives\n LV<\/jats:styled-content>\n hypertrophy and promotes early aortic valve lesions, possibly mediated by valvular in\u00a0situ leptin synthesis. Clinical implementation of local leptin antagonist therapy may attenuate Ang\n II<\/jats:styled-content>\n \u2010induced\n ATAA<\/jats:styled-content>\n and moderate related\n LV<\/jats:styled-content>\n hypertrophy and pre\u2013aortic valve stenosis lesions.\n <\/jats:p>\n <\/jats:sec>\n \n Clinical Trial Registration<\/jats:title>\n \n URL<\/jats:styled-content>\n :\n https:\/\/www.clinicaltrials.gov\/<\/jats:ext-link>\n . Unique identifier:\n NCT<\/jats:styled-content>\n 00449306.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.116.003474","type":"journal-article","created":{"date-parts":[[2016,5,3]],"date-time":"2016-05-03T22:09:06Z","timestamp":1462313346000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Local Application of Leptin Antagonist Attenuates Angiotensin II\u2013Induced Ascending Aortic Aneurysm and Cardiac Remodeling"],"prefix":"10.1161","volume":"5","author":[{"given":"Danny","family":"Ben\u2010Zvi","sequence":"first","affiliation":[{"name":"Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naphtali","family":"Savion","sequence":"additional","affiliation":[{"name":"Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 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Cardiac Surgery, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehud","family":"Raanani","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Lavee","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shlomo","family":"Kotev Emeth","sequence":"additional","affiliation":[{"name":"Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 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