Aneurysm Severity is Increased by Combined Mmp-7 Deletion and N-cadherin Mimetic (EC4-Fc) Over-Expression

Cressida A Lyon, Helen Williams, Rosaria Bianco, Steven J Simmonds, Bethan A Brown, Kerry S Wadey, Frank C T Smith, Jason L Johnson, Sarah J George

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

There is an unmet need for treatments to reduce abdominal aortic aneurysm (AAA) progression. Vascular smooth muscle cell (VSMC) apoptosis precipitates AAA formation, whereas VSMC proliferation repairs the vessel wall. We previously demonstrated that over-expression of EC4-Fc (truncated N-cadherin), or deletion of matrix-metalloproteinase-7 (Mmp-7) reduced VSMC apoptosis in mouse atherosclerotic plaques. Additionally, MMP-7 promotes VSMC apoptosis by cleavage of N-cadherin. We investigated their combined effect on AAA formation. Increased apoptosis and proliferation were observed in human AAA (HAAA) sections compared to normal aortae (HA). This coincided with increased MMP-7 activity and reduced N-cadherin protein levels in HAAA sections compared to HA. Using a mouse model of aneurysm formation, we showed that the combination of Mmp-7 deletion and EC4-Fc overexpression significantly increased AAA severity. Medial apoptosis and proliferation were both significantly reduced in these mice compared to control mice. In vitro, MMP-7 inhibition and EC4-Fc administration significantly supressed human aortic VSMC apoptosis (via activation of PI-3 kinase/Akt signalling) and proliferation. In conclusion, combined Mmp-7 deletion and systemic over-expression of EC4-Fc reduced both proliferation and apoptosis. Reduced proliferation-mediated repair over-rides any benefit of reduced apoptosis, increasing aneurysm severity. Future studies should therefore focus on retarding VSMC apoptosis whilst promoting VSMC proliferation.

Original languageEnglish
Article number17432
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 11 Dec 2017

Keywords

  • Angiotensin II/adverse effects
  • Animals
  • Aorta/metabolism
  • Aortic Aneurysm, Abdominal/etiology
  • Apolipoproteins E/genetics
  • Apoptosis
  • Cadherins/genetics
  • Cell Proliferation
  • Disease Models, Animal
  • Humans
  • Male
  • Matrix Metalloproteinase 7/physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Severity of Illness Index
  • Signal Transduction

Cite this

Lyon, C. A., Williams, H., Bianco, R., Simmonds, S. J., Brown, B. A., Wadey, K. S., Smith, F. C. T., Johnson, J. L., & George, S. J. (2017). Aneurysm Severity is Increased by Combined Mmp-7 Deletion and N-cadherin Mimetic (EC4-Fc) Over-Expression. Scientific Reports, 7(1), [17432]. https://doi.org/10.1038/s41598-017-17700-8