MMP-2 Regulates Erk1/2 phosphorylation and aortic dilatation in marfan syndrome

Wanfen Xiong, Trevor Meisinger, Rebecca Knispel, Jennifer M. Worth, Bernard Timothy Baxter

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Rationale: Aneurysm and dissection of the ascending thoracic aorta are the main cardiovascular complications of Marfan syndrome (MFS) resulting in premature death. Studies using mouse models of MFS have shown that activation of transforming growth factor-beta (TGF-β) and the concomitant upregulation of matrix metalloproteinases (MMPs) contribute to aneurysm development. Our previous study showed that doxycycline delayed aneurysm rupture in a mouse model of MFS, Fbn1 mgR/mgR. Losartan has been shown to prevent aneurysms in another mouse model of MFS, Fbn1 C1039G/+, through inhibition of the Erk1/2 pathway. However, the role of MMP-2 in MFS and effect of losartan on the lifespan of MFS mice remain unknown. Objective: We investigated the role of MMP-2 in MFS and compared the effects of losartan and doxycycline on aortic dilatation and survival in Fbn1mgR/mgR mice. Methods and Results: By life table analysis, we found that losartan and doxycycline improved the survival of Fbn1 mice. Gelatin zymography and Western blot data showed that only doxycycline inhibited MMP-2 expression, whereas both drugs decreased Erk1/2 phosphorylation. When combined, only one of nine mice died within the 30-week study; aortic histology and diameter were normalized and the effects on Smad2 phosphorylation was additive. To further explore the role of MMP-2 in MFS, we created MMP-2-deficient Fbn1mgR/mgR mice. MMP-2 deletion inhibited activation of TGF-β and phosphorylation of Erk1/2 and Smad2 and prolonged the lifespan of the mice. Conclusions: These studies demonstrated that inhibition of MMP-2 by doxycycline delayed the manifestations of MFS, in part, through its ability to decrease active TGF-β and the noncanonical signaling cascade downstream of TGF-β. This study further suggested that targeting TGF-β signaling at different points might be a more effective strategy for inhibiting disease progression.

Original languageEnglish (US)
JournalCirculation Research
Volume110
Issue number12
DOIs
StatePublished - Jun 8 2012

Fingerprint

Marfan Syndrome
Matrix Metalloproteinase 2
Dilatation
Phosphorylation
Doxycycline
Transforming Growth Factor beta
Losartan
Aneurysm
Premature Mortality
Life Tables
Gelatin
Matrix Metalloproteinases
Thoracic Aorta
Aorta
Disease Progression
Dissection
Rupture
Histology
Up-Regulation
Western Blotting

Keywords

  • Aortic aneurysms
  • Doxycycline
  • Losartan
  • Marfan syndrome
  • Matrix metalloproteinases
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

MMP-2 Regulates Erk1/2 phosphorylation and aortic dilatation in marfan syndrome. / Xiong, Wanfen; Meisinger, Trevor; Knispel, Rebecca; Worth, Jennifer M.; Baxter, Bernard Timothy.

In: Circulation Research, Vol. 110, No. 12, 08.06.2012.

Research output: Contribution to journalArticle

Xiong, Wanfen ; Meisinger, Trevor ; Knispel, Rebecca ; Worth, Jennifer M. ; Baxter, Bernard Timothy. / MMP-2 Regulates Erk1/2 phosphorylation and aortic dilatation in marfan syndrome. In: Circulation Research. 2012 ; Vol. 110, No. 12.
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AB - Rationale: Aneurysm and dissection of the ascending thoracic aorta are the main cardiovascular complications of Marfan syndrome (MFS) resulting in premature death. Studies using mouse models of MFS have shown that activation of transforming growth factor-beta (TGF-β) and the concomitant upregulation of matrix metalloproteinases (MMPs) contribute to aneurysm development. Our previous study showed that doxycycline delayed aneurysm rupture in a mouse model of MFS, Fbn1 mgR/mgR. Losartan has been shown to prevent aneurysms in another mouse model of MFS, Fbn1 C1039G/+, through inhibition of the Erk1/2 pathway. However, the role of MMP-2 in MFS and effect of losartan on the lifespan of MFS mice remain unknown. Objective: We investigated the role of MMP-2 in MFS and compared the effects of losartan and doxycycline on aortic dilatation and survival in Fbn1mgR/mgR mice. Methods and Results: By life table analysis, we found that losartan and doxycycline improved the survival of Fbn1 mice. Gelatin zymography and Western blot data showed that only doxycycline inhibited MMP-2 expression, whereas both drugs decreased Erk1/2 phosphorylation. When combined, only one of nine mice died within the 30-week study; aortic histology and diameter were normalized and the effects on Smad2 phosphorylation was additive. To further explore the role of MMP-2 in MFS, we created MMP-2-deficient Fbn1mgR/mgR mice. MMP-2 deletion inhibited activation of TGF-β and phosphorylation of Erk1/2 and Smad2 and prolonged the lifespan of the mice. Conclusions: These studies demonstrated that inhibition of MMP-2 by doxycycline delayed the manifestations of MFS, in part, through its ability to decrease active TGF-β and the noncanonical signaling cascade downstream of TGF-β. This study further suggested that targeting TGF-β signaling at different points might be a more effective strategy for inhibiting disease progression.

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