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.
Bibliographical noteFunding Information:
This study was funded by a private philanthropic donation to Schneiderman through Brigham and Women’s Hospital, Boston, MA; RO1 DK094434-04 to Virmani at CVpath, Gaithersburg, MD; and a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft; Scha808/7-1) to Sch€afer. D. Ben-Zvi was supported by Yad Hanadiv postdoctoral fellowship and by HFSP post-doctoral fellowship.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
- Angiotensin II
- Aortic aneurysm
- Aortic valve stenosis
- Left ventricular hypertrophy
- Leptin antagonist
- Vascular remodeling