title: Local Application of Leptin Antagonist Attenuates Angiotensin II-Induced Ascending Aortic Aneurysm and Cardiac Remodeling.
abstract: Ascending thoracic aortic aneurysm (ATAA) is driven by angiotensin II (AngII) and contributes to the development of left ventricular (LV) remodeling through aortoventricular coupling. We previously showed that locally available leptin augments AngII-induced abdominal aortic aneurysms in apolipoprotein E-deficient mice. We hypothesized that locally synthesized leptin mediates AngII-induced ATAA.
  
  
  
  Following demonstration of leptin synthesis in samples of human ATAA associated with different etiologies, we modeled in situ leptin expression in apolipoprotein E-deficient mice by applying exogenous leptin on the surface of the ascending aorta. This treatment resulted in local aortic stiffening and dilation, LV hypertrophy, and thickening of aortic/mitral valve leaflets. Similar results were obtained in an AngII-infusion ATAA mouse model. To test the dependence of AngII-induced aortic and LV remodeling on leptin activity, a leptin antagonist was applied to the ascending aorta in AngII-infused mice. Locally applied single low-dose leptin antagonist moderated AngII-induced ascending aortic dilation and protected mice from ATAA rupture. Furthermore, LV 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.
  
  
  
  AngII-induced ATAA is mediated by locally synthesized leptin. Aortoventricular hemodynamic coupling drives LV hypertrophy and promotes early aortic valve lesions, possibly mediated by valvular in situ leptin synthesis. Clinical implementation of local leptin antagonist therapy may attenuate AngII-induced ATAA and moderate related LV hypertrophy and pre-aortic valve stenosis lesions.
  
  
  
  URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00449306.
authors.affiliation: Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA.
authors.forename: Danny
authors.initials: D
authors.lastname: Ben-Zvi
authors.affiliation: Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Naphtali
authors.initials: N
authors.lastname: Savion
authors.affiliation: CVPath Institute, Gaithersburg, MD.
authors.forename: Frank
authors.initials: F
authors.lastname: Kolodgie
authors.affiliation: Cancer Research Laboratory, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Simon
authors.affiliation: Cardiovascular Physiology Core, Brigham and Women's Hospital, Boston, MA.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Fisch
authors.affiliation: Medical Clinic 2, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schäfer
authors.affiliation: Analyze IT Research Institute, Tuval, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Bachner-Hinenzon
authors.affiliation: Cardiovascular Physiology Core, Brigham and Women's Hospital, Boston, MA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Faculty of Agriculture, Food and Environment, Hebrew University, Rehovot, Israel.
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.affiliation: Faculty of Agriculture, Food and Environment, Hebrew University, Rehovot, Israel.
authors.forename: Gili
authors.initials: G
authors.lastname: Solomon
authors.affiliation: Department of Cardiac Surgery, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Erez
authors.initials: E
authors.lastname: Kachel
authors.affiliation: Department of Cardiac Surgery, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Raanani
authors.affiliation: Department of Cardiac Surgery, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: Lavee
authors.affiliation: Goldschleger Eye Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Kotev Emeth
authors.affiliation: CVPath Institute, Gaithersburg, MD.
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard-MIT Division of Health Sciences and Technology, and Harvard Medical School, Boston, MA.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Schoen
authors.affiliation: The Gottesdiener Vascular Biology Laboratory, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Vascular Surgery, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Vascular Surgery Research Laboratory, Department of Vascular and Endovascular Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA jschneid@post.tau.ac.il.
authors.forename: Jacob
authors.initials: J
authors.lastname: Schneiderman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000139:chemically induced / Q000378:metabolism* / Q000601:surgery; D001021:Aortic Valve / Q000166:cytology / Q000378:metabolism*; D001024:Aortic Valve Stenosis / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D000074085:Mice, Knockout, ApoE; D008875:Middle Aged; D059289:Vascular Stiffness / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000633:toxicity; D020257:Ventricular Remodeling / Q000187:drug effects*; D055815:Young Adult
chemical_list: D020738:Leptin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II
keywords: angiotensin II; aortic aneurysm; aortic valve stenosis; left ventricular hypertrophy; leptin; leptin antagonist; vascular remodeling