Aneurysm severity is suppressed by deletion of CCN4: CCN4 in aneurysms

Helen Williams, Kerry S Wadey, Aleksandra Frankow, Hazel C Blythe, Tessa Forbes, Jason L Johnson, Sarah J George*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

1 Citation (Scopus)
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Abstract

Patients with abdominal aortic aneurysms are frequently treated with high-risk surgery. A pharmaceutical treatment to reverse aneurysm progression could prevent the need for surgery and save both lives and healthcare resources. Since CCN4 regulates cell migration, proliferation and apoptosis, processes involved in aneurysm progression, it is a potential regulator of aneurysm progression.
We investigated the role of CCN4 in a mouse aneurysm model, using apolipoprotein-E knockout (ApoE-/-) mice fed high fat diet and infused with Angiotensin II (AngII). Blood pressure was similarly elevated in CCN4-/-ApoE-/- mice and CCN4+/+ApoE-/- mice (controls) in response to AngII infusion. Deletion of CCN4 significantly reduced the number of ruptured aortae, both thoracic and abdominal aortic area, and aneurysm grade score, compared to controls. Additionally, the frequency of vessel wall remodelling and the number of elastic lamina breaks was significantly suppressed in CCN4-/-ApoE-/- mice compared to controls. Immunohistochemistry revealed a significantly lower proportion of macrophages, while the proportion of smooth muscle cells was not affected by the deletion of CCN4. There was also a reduction in both proliferation and apoptosis in CCN4-/-ApoE-/- mice compared to controls. In vitro studies showed that CCN4 significantly increased monocyte adhesion beyond that seen with TNF and stimulated macrophage migration by more than 3-fold.
In summary, absence of CCN4 reduced aneurysm severity and improved aortic integrity, which may be the result of reduced macrophage infiltration and cell apoptosis. Inhibition of CCN4 could offer a potential therapeutic approach for the treatment of aneurysms.
Original languageEnglish
Pages (from-to)421-432
Number of pages12
JournalJournal of Cell Communication and Signaling
Volume15
Issue number3
Early online date2 Jun 2021
DOIs
Publication statusPublished - Sep 2021

Bibliographical note

Funding Information:
CCN4 knockout mice were a kind gift from Marian Young, NIH, Bethesda, Maryland. The project was funded by the British Heart Foundation (PG/14/67/31030).

Funding Information:
CCN4 knockout mice were a kind gift from Marian Young, NIH, Bethesda, Maryland. The project was funded by the British Heart Foundation (PG/14/67/31030).

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • CCN-4
  • WISP-1
  • WISP1
  • aneurysm
  • atherosclerosis
  • Wnt pathway

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