Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice

Yoshito Yamashiro, Christina L. Papke, Jungsil Kim, Lea Jeanne Ringuette, Qing Jun Zhang, Zhi Ping Liu, Hamid Mirzaei, Jessica E. Wagenseil, Elaine C. Davis, Hiromi Yanagisawa

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4(SMKO) mice with an SMC-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin-converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4(SMKO) aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 (SSH1) phosphatase, an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also, by P7, biomechanical changes and underdeveloped elastic lamina-SMC connections were evident, and the abundance of early growth response 1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina-SMC connections. Phosphoinositide 3-kinase (PI3K) is involved in the angiotensin II-mediated activation of SSH1, and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina-SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms.

Original languageEnglish (US)
Pages (from-to)ra105
JournalScience Signaling
Volume8
Issue number399
DOIs
StatePublished - Oct 20 2015

Fingerprint

Actin Depolymerizing Factors
Aortic Aneurysm
Smooth Muscle Myocytes
Muscle
Chemical activation
Aneurysm
Peptidyl-Dipeptidase A
1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Angiotensin II
Extracellular Matrix
Cofilin 1
Destrin
Phosphotransferases
Gene Deletion
Phosphoric Monoester Hydrolases
Proteomics
Blood Vessels
Aorta
Actins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice. / Yamashiro, Yoshito; Papke, Christina L.; Kim, Jungsil; Ringuette, Lea Jeanne; Zhang, Qing Jun; Liu, Zhi Ping; Mirzaei, Hamid; Wagenseil, Jessica E.; Davis, Elaine C.; Yanagisawa, Hiromi.

In: Science Signaling, Vol. 8, No. 399, 20.10.2015, p. ra105.

Research output: Contribution to journalArticle

Yamashiro, Y, Papke, CL, Kim, J, Ringuette, LJ, Zhang, QJ, Liu, ZP, Mirzaei, H, Wagenseil, JE, Davis, EC & Yanagisawa, H 2015, 'Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice', Science Signaling, vol. 8, no. 399, pp. ra105. https://doi.org/10.1126/scisignal.aab3141
Yamashiro, Yoshito ; Papke, Christina L. ; Kim, Jungsil ; Ringuette, Lea Jeanne ; Zhang, Qing Jun ; Liu, Zhi Ping ; Mirzaei, Hamid ; Wagenseil, Jessica E. ; Davis, Elaine C. ; Yanagisawa, Hiromi. / Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice. In: Science Signaling. 2015 ; Vol. 8, No. 399. pp. ra105.
@article{8b30fd1303c745759698369cbc2f355a,
title = "Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice",
abstract = "Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4(SMKO) mice with an SMC-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin-converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4(SMKO) aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 (SSH1) phosphatase, an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also, by P7, biomechanical changes and underdeveloped elastic lamina-SMC connections were evident, and the abundance of early growth response 1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina-SMC connections. Phosphoinositide 3-kinase (PI3K) is involved in the angiotensin II-mediated activation of SSH1, and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina-SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms.",
author = "Yoshito Yamashiro and Papke, {Christina L.} and Jungsil Kim and Ringuette, {Lea Jeanne} and Zhang, {Qing Jun} and Liu, {Zhi Ping} and Hamid Mirzaei and Wagenseil, {Jessica E.} and Davis, {Elaine C.} and Hiromi Yanagisawa",
year = "2015",
month = "10",
day = "20",
doi = "10.1126/scisignal.aab3141",
language = "English (US)",
volume = "8",
pages = "ra105",
journal = "Science Signaling",
issn = "1937-9145",
publisher = "American Association for the Advancement of Science",
number = "399",

}

TY - JOUR

T1 - Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice

AU - Yamashiro, Yoshito

AU - Papke, Christina L.

AU - Kim, Jungsil

AU - Ringuette, Lea Jeanne

AU - Zhang, Qing Jun

AU - Liu, Zhi Ping

AU - Mirzaei, Hamid

AU - Wagenseil, Jessica E.

AU - Davis, Elaine C.

AU - Yanagisawa, Hiromi

PY - 2015/10/20

Y1 - 2015/10/20

N2 - Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4(SMKO) mice with an SMC-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin-converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4(SMKO) aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 (SSH1) phosphatase, an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also, by P7, biomechanical changes and underdeveloped elastic lamina-SMC connections were evident, and the abundance of early growth response 1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina-SMC connections. Phosphoinositide 3-kinase (PI3K) is involved in the angiotensin II-mediated activation of SSH1, and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina-SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms.

AB - Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4(SMKO) mice with an SMC-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin-converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4(SMKO) aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 (SSH1) phosphatase, an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also, by P7, biomechanical changes and underdeveloped elastic lamina-SMC connections were evident, and the abundance of early growth response 1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina-SMC connections. Phosphoinositide 3-kinase (PI3K) is involved in the angiotensin II-mediated activation of SSH1, and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina-SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms.

UR - http://www.scopus.com/inward/record.url?scp=84974834626&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84974834626&partnerID=8YFLogxK

U2 - 10.1126/scisignal.aab3141

DO - 10.1126/scisignal.aab3141

M3 - Article

C2 - 26486174

AN - SCOPUS:84974834626

VL - 8

SP - ra105

JO - Science Signaling

JF - Science Signaling

SN - 1937-9145

IS - 399

ER -