Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice

Jianbin Huang, Yoshito Yamashiro, Christina L. Papke, Yuichi Ikeda, Yanling Lin, Miteshkumar Patel, Tadashi Inagami, Victoria P. Le, Jessica E. Wagenseil, Hiromi Yanagisawa

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4SMKO) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4SMKO mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4SMKO mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype.

Original languageEnglish (US)
JournalScience Translational Medicine
Volume5
Issue number183
DOIs
StatePublished - May 1 2013

Fingerprint

Enzyme Activation
Aortic Aneurysm
Angiotensins
Peptidyl-Dipeptidase A
Smooth Muscle Myocytes
Aneurysm
Blood Vessels
Losartan
Angiotensin II
Angiotensin Type 2 Receptor
Pharmacology
Phenotype
Contractile Proteins
Marfan Syndrome
Captopril
Therapeutic Uses
Connective Tissue
Up-Regulation
Maintenance
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice. / Huang, Jianbin; Yamashiro, Yoshito; Papke, Christina L.; Ikeda, Yuichi; Lin, Yanling; Patel, Miteshkumar; Inagami, Tadashi; Le, Victoria P.; Wagenseil, Jessica E.; Yanagisawa, Hiromi.

In: Science Translational Medicine, Vol. 5, No. 183, 01.05.2013.

Research output: Contribution to journalArticle

Huang, Jianbin ; Yamashiro, Yoshito ; Papke, Christina L. ; Ikeda, Yuichi ; Lin, Yanling ; Patel, Miteshkumar ; Inagami, Tadashi ; Le, Victoria P. ; Wagenseil, Jessica E. ; Yanagisawa, Hiromi. / Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice. In: Science Translational Medicine. 2013 ; Vol. 5, No. 183.
@article{26cc74abea9e4dba994fca75fe8b0a9a,
title = "Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice",
abstract = "Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4SMKO) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4SMKO mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4SMKO mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype.",
author = "Jianbin Huang and Yoshito Yamashiro and Papke, {Christina L.} and Yuichi Ikeda and Yanling Lin and Miteshkumar Patel and Tadashi Inagami and Le, {Victoria P.} and Wagenseil, {Jessica E.} and Hiromi Yanagisawa",
year = "2013",
month = "5",
day = "1",
doi = "10.1126/scitranslmed.3005025",
language = "English (US)",
volume = "5",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "183",

}

TY - JOUR

T1 - Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice

AU - Huang, Jianbin

AU - Yamashiro, Yoshito

AU - Papke, Christina L.

AU - Ikeda, Yuichi

AU - Lin, Yanling

AU - Patel, Miteshkumar

AU - Inagami, Tadashi

AU - Le, Victoria P.

AU - Wagenseil, Jessica E.

AU - Yanagisawa, Hiromi

PY - 2013/5/1

Y1 - 2013/5/1

N2 - Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4SMKO) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4SMKO mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4SMKO mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype.

AB - Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4SMKO) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4SMKO mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4SMKO mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype.

UR - http://www.scopus.com/inward/record.url?scp=84878267172&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878267172&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.3005025

DO - 10.1126/scitranslmed.3005025

M3 - Article

C2 - 23636094

AN - SCOPUS:84878267172

VL - 5

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 183

ER -