Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

Autor: Frederick J. Schoen, Katrin Schäfer, Naphtali Savion, Arieh Gertler, Noa Bachner-Hinenzon, Erez Kachel, Jacob Schneiderman, Danny Ben-Zvi, Gili Solomon, Amos J. Simon, Sudeshna Fisch, Jacob Lavee, Xin Cao, Renu Virmani, Frank D. Kolodgie, Shlomo Kotev Emeth, Ehud Raanani
Rok vydání: 2016
Předmět:
Leptin
Male
0301 basic medicine
Aortic valve
Translational Studies
Mice
Knockout
ApoE
aortic valve stenosis
angiotensin II
030204 cardiovascular system & hematology
Left ventricular hypertrophy
Vascular Medicine
Mice
Aortic aneurysm
0302 clinical medicine
Vasoconstrictor Agents
Medicine
Cells
Cultured
Original Research
Aged
80 and over
Ventricular Remodeling
digestive
oral
and skin physiology
Middle Aged
left ventricular hypertrophy
medicine.anatomical_structure
Aortic Valve
Aortic valve stenosis
cardiovascular system
Cardiology
Female
Hypertrophy
Left Ventricular
Cardiology and Cardiovascular Medicine
aortic aneurysm
hormones
hormone substitutes
and hormone antagonists
Adult
medicine.medical_specialty
vascular remodeling
Thoracic aortic aneurysm
Young Adult
03 medical and health sciences
Vascular Stiffness
medicine.artery
Internal medicine
Ascending aorta
Animals
Humans
Aged
Cell Proliferation
Aortic Aneurysm
Thoracic
business.industry
leptin antagonist
medicine.disease
Aneurysm
Angiotensin II
030104 developmental biology
Endocrinology
Animal Models of Human Disease
Valvular Heart Disease
business
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
DOI: 10.1161/jaha.116.003474
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: