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

Abstract

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 transforming growth factor-β signaling, is upregulated in diabetes. We hypothesized that CDA1 plays a key role in conferring the protective effect of diabetes against aortic aneurysms. Male wild-type, CDA1 knockout (KO), apolipoprotein 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-β signaling, reduced expression of various collagens, and increased aortic macrophage infiltration and matrix metalloproteinase 12 expression. In the well-characterized model of angiotensin II-induced aneurysm formation, concomitant diabetes reduced fatal aortic rupture and attenuated suprarenal aortic expansion, changes not seen in dKO mice. Furthermore, aortic CDA1 expression was downregulated ∼70% within biopsies from human abdominal aortic aneurysms. The identification that diabetes is associated with upregulation of vascular CDA1 and that CDA1 deletion in diabetic mice promotes aneurysm formation provides evidence that CDA1 plays a role in diabetes to reduce susceptibility to aneurysm formation.

Diabetes and aortic aneurysm: current state of the art

“…Although the direct impact of diabetes on biglycan expression in the aneurysmal aortic wall is still uncertain, diabetes is associated with an upregulation of Cell Division Autoantigen 1 (CDA1) which enhances TGF-β signalling pathway and contributes to the protective effect of diabetes on AAA formation. 37 DM can also alter the production, degradation and deposition of other GAGs in the aorta, with additional consequences on ECM remodelling as well as the structural and physical properties of the arterial wall. Decorin, a small leucin-rich repeat proteoglycan, is increased in response to high-glucose concentration, interacts with TGF-β to regulate matrix organization and collagen matrices and may reduce aneurysm formation in part through modulation of ECM remodelling.…”

Nationwide comparison of long-term survival and cardiovascular morbidity after acute aortic aneurysm repair in patients with and without type 2 diabetes

“…23,24 Hyperglycemia might influence angiogenesis, remodeling, extracellular matrix volume and glycation, advanced glycation end-products, inflammatory markers, oxidative stress, composition of the thrombus commonly present in an AAA, and transforming growth factor b signaling. [23][24][25] Furthermore, hemodynamic features of the aorta might differ between diabetic and nondiabetic patients, and computational fluid dynamic methods are currently evaluated to help understand such mechanisms. 26 Our methodology does not allow us to speculate about these mechanisms, however, as we have not assessed biomarkers.…”

The Role of Cell Division Autoantigen 1 (CDA1) in Renal Fibrosis of Diabetic Nephropathy

“…Studies have also shown that CDA1 appears to be a significant molecule not only in DN but also in other diabetic vascular complications such as atherosclerosis [ 68 ]. Li et al [ 66 ] indicated that CDA1 plays a key role in the protective effect of diabetes on aneurysms. However, the specific mechanism by which CDA1 enhances the TGF- β signaling pathway and promotes renal fibrosis in DN deserves further investigation.…”