6 Sept 2018

Scientists reveal reason why diabetes protects against aneurysms

Three of the study's authors: L-R Dr Tieqao Wu,
Dr Zhong-Lin Chai and Dr Pacific Huynh
by Anne Crawford

For some years clinicians have observed that people with diabetes are usually less likely to have aortic aneurysms than non-diabetic patients. Aortic aneurysm is a major cause of death in older adults.

The phenomenon was puzzling: diabetes is associated with an increased incidence of cardiovascular disease, specifically related to atherosclerosis, hardening of the arteries. Most aortic aneurysms are caused by atherosclerosis, which weakens the blood vessel walls.

Now, Monash University scientists led by Dr Zhong-Lin Chai from the Department of Diabetes have revealed a mechanism that explains the phenomenon.

Dr Chai has shown in a paper published in Diabetes that a molecule called CDA1 (cell
division autoantigen 1) may play a protective role against aneurysm formation. The study
demonstrated that CDA1-deficient mice with diabetes developed aneurysms, but diabetic mice in the presence of CDA1 were protected from severe aneurysms. The study showed in mice that in the absence of CDA1 the blood vessel walls were less strong.

The findings were strengthened when collaborators at James Cook University, Queensland, collected samples from patients with and without aneurysms, and found that the aneurysm samples had CDA1 levels about 70 per cent lower than control samples.

“Diabetes is considered to be a bad thing but it’s doing good here,” Dr Chai said. “We think this is due to fibrosis. Diabetes causes fibrosis in the blood vessel wall which makes the vessel stronger. If the mechanism is due to the increased strength of the wall from fibrosis, if we removed the CDA1 gene in these mice this means diabetes may not increase fibrosis so the vessel wall strength may not be increased. As a result, the diabetes-associated protection may be removed,” he said.

Further, the scientists showed that CDA1 enhanced a protein called TGF-β (transforming
growth factor-beta) which is closely linked to diabetic complications, including atherosclerosis.

“I think these are important findings,” Dr Chai said. “Firstly they explain the observations of diabetes-associated protection against aneurysm. Secondly, they suggest that CDA1 may be a therapeutic target to prevent or retard the progression of human aneurysms.”

Dr Chai has worked on CDA1 trying to find its functions since he identified and named the protein in 2001. “There was no information at all about it so we didn’t know what it did.”
He cloned the gene. Studies carried out by Dr Chai later showed that increasing the concentration of the molecule in cancer cells stopped the cells from dividing and growing.

The findings in the recent study were serendipitous.

“My focus is on kidney disease and kidney fibrosis,” he said. “This data provides an indication that we need to give a very careful consideration or have a more robust examination of the side-effects when we develop the approach to diabetic fibrosis and be careful not to take away the protective properties.”

First author on the paper was then PhD student Jiaze Li. Dr Helen Kiriazis and Associate Professor Xiao-Jun Du from the Baker Institute helped with monitoring the aortic aneurysm growth in live animals using a high-resolution ultrasound imaging technology. The collaborators at James Cook University were led by Professor Jonathan Golledge.

Li J, Huynh P, Dai A, Wu T, Tu Y, Chow B, Kiriazis H, Du XJ, Bach LA, Wilkinson-Berka JL, Biros E, Walker P, Nataatmadja M, West M, Golledge J, Allen TJ, Cooper ME, Chai Z. Diabetes Reduces Severity of Aortic Aneurysms Depending on the Presence of Cell Division Autoantigen 1 (CDA1). Diabetes. 2018 Apr;67(4):755-768. doi: 10.2337/db17-0134. Epub 2018 Jan 8.

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