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RESEARCH PRODUCT
Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling
Frederick J. SchoenKatrin SchäferNaphtali SavionArieh GertlerNoa Bachner-hinenzonErez KachelJacob SchneidermanJacob SchneidermanDanny Ben-zviGili SolomonAmos J. SimonSudeshna FischJacob LaveeXin CaoRenu VirmaniFrank D. KolodgieShlomo Kotev EmethEhud Raananisubject
LeptinMale0301 basic medicineAortic valveTranslational StudiesMice Knockout ApoEaortic valve stenosisangiotensin II030204 cardiovascular system & hematologyLeft ventricular hypertrophyVascular MedicineMiceAortic aneurysm0302 clinical medicineVasoconstrictor AgentsMedicineCells CulturedOriginal ResearchAged 80 and overVentricular RemodelingLeptindigestive oral and skin physiologyMiddle Agedleft ventricular hypertrophymedicine.anatomical_structureAortic ValveAortic valve stenosiscardiovascular systemCardiologyFemaleHypertrophy Left VentricularCardiology and Cardiovascular Medicineaortic aneurysmhormones hormone substitutes and hormone antagonistsAdultmedicine.medical_specialtyvascular remodelingThoracic aortic aneurysmYoung Adult03 medical and health sciencesVascular Stiffnessmedicine.arteryInternal medicineAscending aortaAnimalsHumansAgedCell ProliferationAortic Aneurysm Thoracicbusiness.industryleptin antagonistmedicine.diseaseAneurysmAngiotensin II030104 developmental biologyEndocrinologyAnimal Models of Human DiseaseValvular Heart Diseasebusinessdescription
Background Ascending thoracic aortic aneurysm ( ATAA ) is driven by angiotensin II (Ang II ) and contributes to the development of left ventricular ( LV ) remodeling through aortoventricular coupling. We previously showed that locally available leptin augments Ang II ‐induced abdominal aortic aneurysms in apolipoprotein E–deficient mice. We hypothesized that locally synthesized leptin mediates Ang II ‐induced ATAA . Methods and Results 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 Ang II ‐infusion ATAA mouse model. To test the dependence of Ang II ‐induced aortic and LV remodeling on leptin activity, a leptin antagonist was applied to the ascending aorta in Ang II ‐infused mice. Locally applied single low‐dose leptin antagonist moderated Ang II ‐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. Conclusions Ang II ‐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 Ang II ‐induced ATAA and moderate related LV hypertrophy and pre–aortic valve stenosis lesions. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 00449306.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-05-05 | Journal of the American Heart Association |