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 TNFα and stimulated macrophage migration by more than threefold. 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.
Highlights
Abdominal aortic aneurysms occur when the wall of the aorta loses integrity, leading to the aorta bulging from a normal diameter of 2 cm, to more than 3 cm
As we expected infusion of Angiotensin II (AngII) significantly increased systolic, diastolic and mean blood pressure in both the CCN4−/−ApoE−/− knockout mice and C CN4+/+ApoE−/− controls (Fig. 1)
This study illustrates that deletion of CCN4 leads to a retardation of aneurysm progression in the thoracic and abdominal aortae of A poE−/− knockout mice
Summary
Abdominal aortic aneurysms occur when the wall of the aorta loses integrity, leading to the aorta bulging from a normal diameter of 2 cm, to more than 3 cm. Aneurysms are surgically treated when their diameter exceeds 5.5 cm, as they are considered to have a high risk of rupture (Aggarwal et al 2011). CCN4 is a secreted signalling protein member of the CCN family (Perbal and Perbal 2016) and is a Wnt signalling pathway target gene and is sometimes referred to as WISP-1. It has various effects on cell behaviour, including being pro-adhesion, migration, proliferation, differentiation and survival (Jun and Lau 2011; Liu et al 2013a, b). CCN3 has been shown to protect against aneurysms (Zhang et al 2016), with overexpression viruses lessening the severity of disease, while knockout of CCN3 increased aneurysm severity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
