Localized antileptin therapy prevents aortic root dilatation and preserves left ventricular systolic function in a murine model of marfan syndrome

Sudeshna Fisch, Noa Bachner-Hinenzon, Offir Ertracht, Liang Guo, Yhara Arad, Danny Ben-Zvi, Ronglih Liao, Jacob Schneiderman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

BACKGROUND: Marfan syndrome (MFS) is a genetically transmitted connective tissue disorder characterized by aortic root dilatation, dissection, and rupture. Molecularly, MFS pathological features have been shown to be driven by increased angiotensin II in the aortic wall. Using an angiotensin II–driven aneurysm mouse model, we have recently demonstrated that local inhibition of leptin activity restricts aneurysm formation in the ascending and abdominal aorta. As we observed de novo leptin synthesis in the ascending aortic aneurysm wall of patients with MFS, we hypothesized that local counteracting of leptin activity in MFS may also prevent aortic cardiovascular complications in this context. METHODS AND RESULTS: Fbn1C1039G/+ mice underwent periaortic application of low-dose leptin antagonist at the aortic root. Treatment abolished medial degeneration and prevented increase in aortic root diameter (P<0.001). High levels of leptin, transforming growth factor β1, Phosphorylated Small mothers against decapentaplegic 2, and angiotensin-converting enzyme 1 observed in saline-treated MFS mice were downregulated in leptin antagonist–treated animals (P<0.01, P<0.05, P<0.001, and P<0.001, respectively). Leptin and angiotensin-converting enzyme 1 expression levels in left ventricular cardiomyocytes were also decreased (P<0.001) and coincided with prevention of left ventricular hypertrophy and aortic and mitral valve leaflet thickening (P<0.01 and P<0.05, respectively) and systolic function preservation. CONCLUSIONS: Local, periaortic application of leptin antagonist prevented aortic root dilatation and left ventricular valve remodeling, preserving left ventricular systolic function in an MFS mouse model. Our results suggest that local inhibition of leptin may constitute a novel, stand-alone approach to prevent MFS aortic root aneurysms and potentially other similar angiotensin II–driven aortic pathological features.

Original languageAmerican English
Article numbere014761
JournalJournal of the American Heart Association
Volume9
Issue number10
DOIs
StatePublished - 18 May 2020

Bibliographical note

Publisher Copyright:
© 2020 The Authors.

Keywords

  • Aortic aneurysm
  • Leptin antagonist
  • Local therapy
  • Marfan syndrome
  • Systolic dysfunction

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