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Local Application of Leptin Antagonist Attenuates Angiotensin II-Induced Ascending Aortic Aneurysm and Cardiac Remodeling
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نویسنده
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ben-zvi d. ,savion n. ,kolodgie f. ,simon a. ,fisch s. ,schäfer k. ,bachner-hinenzon n. ,cao x. ,gertler a. ,solomon g. ,kachel e. ,raanani e. ,lavee j. ,kotev emeth s. ,virmani r. ,schoen f.j. ,schneiderman j.
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منبع
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journal of the american heart association - 2016 - دوره : 5 - شماره : 5
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چکیده
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Background: 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. 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 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. conclusions: 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. © 2016 the authors. published on behalf of the american heart association,inc.,by wiley blackwell.
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کلیدواژه
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Angiotensin II; Aortic aneurysm; Aortic valve stenosis; Left ventricular hypertrophy; Leptin; Leptin antagonist; Vascular remodeling
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آدرس
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stem cell and regenerative biology,harvard university,cambridge,ma, United States, goldschleger eye research institute,sackler faculty of medicine,tel aviv university,tel aviv, Israel, cvpath institute,gaithersburg,md, United States, cancer research laboratory,sheba medical center,sackler faculty of medicine,tel aviv university,tel aviv, Israel, cardiovascular physiology core,brigham and women's hospital,boston,ma, United States, medical clinic 2,university medical center,johannes gutenberg-university mainz,mainz, Germany, analyze it research institute,tuval, Israel, cardiovascular physiology core,brigham and women's hospital,boston,ma, United States, faculty of agriculture,food and environment,hebrew university,rehovot, Israel, faculty of agriculture,food and environment,hebrew university,rehovot, Israel, department of cardiac surgery,sheba medical center,sackler faculty of medicine,tel aviv university,tel aviv, Israel, department of cardiac surgery,sheba medical center,sackler faculty of medicine,tel aviv university,tel aviv, Israel, department of cardiac surgery,sheba medical center,sackler faculty of medicine,tel aviv university,tel aviv, Israel, goldschleger eye research institute,sackler faculty of medicine,tel aviv university,tel aviv, Israel, cvpath institute,gaithersburg,md, United States, department of pathology,brigham and women's hospital,harvard-mit division of health sciences and technology,and harvard medical school,boston,ma, United States, 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, United States
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Authors
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