Diabetes Reduces Severity of Aortic Aneurysms Depending on the Presence of Cell Division Autoantigen 1 (CDA1)

Jiaze Li, Pacific Huynh, Aozhi Dai, Tieqiao Wu, Yugang Tu, Bryna Chow, Helen Kiriazis, Xiao-Jun Du, Leon A. Bach, Jennifer L. Wilkinson-Berka, Erik Biros, Philip Walker, Maria Nataatmadja, Malcolm West, Jonathan Golledge, Terri J. Allen, Mark E. Cooper, Zhonglin Chai
Diabetes is a negative risk factor for aortic aneurysm, but the underlying explanation for this phenomenon is unknown. We have previously demonstrated that cell division autoantigen 1 (CDA1), which enhances transfor- ming growth factor-b signaling, is upregulated in dia- betes. We hypothesized that CDA1 plays a key role in conferring the protective effect of diabetes against aortic aneurysms. Male wild-type,CDA1 knockout (KO), apolipo- protein E (ApoE) KO, and CDA1/ApoE double-KO (dKO) mice were rendered diabetic. Whereas aneurysms were not observed in diabetic ApoE KO and wild-type mice, 40% of diabetic dKO mice developed aortic aneurysms. These aneurysms were associated with attenuated aortic transforming growth factor-b signaling, reduced expres- sion of various collagens, and increased aortic mac- rophage infiltration and matrix metalloproteinase 12 expression. In the well-characterized model of an- giotensin II–induced aneurysm formation, concomitant diabetes reduced fatal aortic rupture and attenuated su- prarenal aortic expansion, changes not seen in dKOmice. Furthermore, aortic CDA1 expression was downregu- lated ∼70% within biopsies from human abdominal aortic aneurysms. The identification that diabetes is associated with upregulation of vascular CDA1 and that CDA1 dele- tion in diabetic mice promotes aneurysm formation pro- vides evidence that CDA1 plays a role in diabetes to reduce susceptibility to aneurysm formation.

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