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

doi:10.1161/JAHA.119.014761

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

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

3 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: Fbn1^C1039G/+ 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 language	American English
Article number	e014761
Journal	Journal of the American Heart Association
Volume	9
Issue number	10
DOIs	https://doi.org/10.1161/JAHA.119.014761
State	Published - 18 May 2020

Bibliographical note

Funding Information:
We are grateful to Fred Roberts, from FujiFilm VisualSonics, Inc, for generous technical support and to Teresa Bowman, from the Specialized Histopathology Core, Brigham and Women’s Hospital, Department of Pathology, Boston, MA, for dedicated histological analyses. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histological and immunohistochemistry services. Dana-Farber/Harvard Cancer Center is supported in part by a National Cancer Institute Cancer Center Support Grant NIH 5 P30 CA06516. We thank Ming Tao from the Department of Vascular and Endovascular Surgery, Brigham and Women Hospital, Boston, MA, for technical support. We also thank Jonathan I. Schneiderman, PhD, for his critical review of the manuscript.

Funding Information:
This work was funded by a private donation from Nathan Gottesdiener. We are grateful to Fred Roberts, from FujiFilm VisualSonics, Inc, for generous technical support and to Teresa Bowman, from the Specialized Histopathology Core, Brigham and Women?s Hospital, Department of Pathology, Boston, MA, for dedicated histological analyses. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histological and immunohistochemistry services. DanaFarber/Harvard Cancer Center is supported in part by a National Cancer Institute Cancer Center Support Grant NIH 5 P30 CA06516. We thank Ming Tao from the Department of Vascular and Endovascular Surgery, Brigham and Women Hospital, Boston, MA, for technical support. We also thank Jonathan I. Schneiderman, PhD, for his critical review of the manuscript.

Publisher Copyright:
© 2020 The Authors.

Keywords

Aortic aneurysm
Leptin antagonist
Local therapy
Marfan syndrome
Systolic dysfunction

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10.1161/JAHA.119.014761

Cite this

Fisch, S., Bachner-Hinenzon, N., Ertracht, O., Guo, L., Arad, Y., Ben-Zvi, D., Liao, R., & Schneiderman, J. (2020). Localized antileptin therapy prevents aortic root dilatation and preserves left ventricular systolic function in a murine model of marfan syndrome. Journal of the American Heart Association, 9(10), Article e014761. https://doi.org/10.1161/JAHA.119.014761

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

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.",

keywords = "Aortic aneurysm, Leptin antagonist, Local therapy, Marfan syndrome, Systolic dysfunction",

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

note = "Funding Information: We are grateful to Fred Roberts, from FujiFilm VisualSonics, Inc, for generous technical support and to Teresa Bowman, from the Specialized Histopathology Core, Brigham and Women{\textquoteright}s Hospital, Department of Pathology, Boston, MA, for dedicated histological analyses. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histological and immunohistochemistry services. Dana-Farber/Harvard Cancer Center is supported in part by a National Cancer Institute Cancer Center Support Grant NIH 5 P30 CA06516. We thank Ming Tao from the Department of Vascular and Endovascular Surgery, Brigham and Women Hospital, Boston, MA, for technical support. We also thank Jonathan I. Schneiderman, PhD, for his critical review of the manuscript. Funding Information: This work was funded by a private donation from Nathan Gottesdiener. We are grateful to Fred Roberts, from FujiFilm VisualSonics, Inc, for generous technical support and to Teresa Bowman, from the Specialized Histopathology Core, Brigham and Women?s Hospital, Department of Pathology, Boston, MA, for dedicated histological analyses. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histological and immunohistochemistry services. DanaFarber/Harvard Cancer Center is supported in part by a National Cancer Institute Cancer Center Support Grant NIH 5 P30 CA06516. We thank Ming Tao from the Department of Vascular and Endovascular Surgery, Brigham and Women Hospital, Boston, MA, for technical support. We also thank Jonathan I. Schneiderman, PhD, for his critical review of the manuscript. Publisher Copyright: {\textcopyright} 2020 The Authors.",

year = "2020",

month = may,

day = "18",

doi = "10.1161/JAHA.119.014761",

language = "American English",

volume = "9",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "10",

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TY - JOUR

T1 - Localized antileptin therapy prevents aortic root dilatation and preserves left ventricular systolic function in a murine model of marfan syndrome

AU - Fisch, Sudeshna

AU - Bachner-Hinenzon, Noa

AU - Ertracht, Offir

AU - Guo, Liang

AU - Arad, Yhara

AU - Ben-Zvi, Danny

AU - Liao, Ronglih

AU - Schneiderman, Jacob

N1 - Funding Information: We are grateful to Fred Roberts, from FujiFilm VisualSonics, Inc, for generous technical support and to Teresa Bowman, from the Specialized Histopathology Core, Brigham and Women’s Hospital, Department of Pathology, Boston, MA, for dedicated histological analyses. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histological and immunohistochemistry services. Dana-Farber/Harvard Cancer Center is supported in part by a National Cancer Institute Cancer Center Support Grant NIH 5 P30 CA06516. We thank Ming Tao from the Department of Vascular and Endovascular Surgery, Brigham and Women Hospital, Boston, MA, for technical support. We also thank Jonathan I. Schneiderman, PhD, for his critical review of the manuscript. Funding Information: This work was funded by a private donation from Nathan Gottesdiener. We are grateful to Fred Roberts, from FujiFilm VisualSonics, Inc, for generous technical support and to Teresa Bowman, from the Specialized Histopathology Core, Brigham and Women?s Hospital, Department of Pathology, Boston, MA, for dedicated histological analyses. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histological and immunohistochemistry services. DanaFarber/Harvard Cancer Center is supported in part by a National Cancer Institute Cancer Center Support Grant NIH 5 P30 CA06516. We thank Ming Tao from the Department of Vascular and Endovascular Surgery, Brigham and Women Hospital, Boston, MA, for technical support. We also thank Jonathan I. Schneiderman, PhD, for his critical review of the manuscript. Publisher Copyright: © 2020 The Authors.

PY - 2020/5/18

Y1 - 2020/5/18

N2 - 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.

AB - 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.

KW - Aortic aneurysm

KW - Leptin antagonist

KW - Local therapy

KW - Marfan syndrome

KW - Systolic dysfunction

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U2 - 10.1161/JAHA.119.014761

DO - 10.1161/JAHA.119.014761

M3 - Article

C2 - 32378446

AN - SCOPUS:85084935571

SN - 2047-9980

VL - 9

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 10

M1 - e014761

ER -

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

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Keywords

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