title: MMP-2 regulates Erk1/2 phosphorylation and aortic dilatation in Marfan syndrome.
abstract: BACKGROUND
  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 Fbn1(mgR/mgR) mice.
  
  
  RESULTS
  By life table analysis, we found that losartan and doxycycline improved the survival of Fbn1(mgR/mgR) 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 Fbn1(mgR/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.
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-7690, USA. wxiong@unmc.edu
authors.forename: Wanfen
authors.initials: W
authors.lastname: Xiong
authors.forename: Trevor
authors.initials: T
authors.lastname: Meisinger
authors.forename: Rebecca
authors.initials: R
authors.lastname: Knispel
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Worth
authors.forename: B Timothy
authors.initials: BT
authors.lastname: Baxter
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology; D018450:Disease Progression; D004318:Doxycycline / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D019808:Losartan / Q000008:administration & dosage; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008382:Marfan Syndrome / Q000188:drug therapy / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D019808:Losartan; D004318:Doxycycline