A potential role for glycated cross-links in abdominal aortic aneurysm disease

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Abstract

Background:

Diabetes is a risk factor for atherosclerotic disease but negatively associated with the development and progression of abdominal aortic aneurysm (AAA). Advanced glycation end products (AGEs) are increased in diabetes and renders the vascular matrix more resistant to proteolysis. We assessed the concentration of AGEs in AAA biopsies obtained from diabetic and nondiabetic patients and hypothesized that (nonenzymatic) glycation of AAA tissue protects against proteolytic breakdown of collagen.

Methods:

AAA biopsies were collected from 30 diabetic and 30 matched nondiabetic AAA patients at the time of open repair. Aortic control samples from 10 nondiabetic and 16 diabetic patients were collected, and concentrations of the AGE cross-link pentosidine was measured. Furthermore, noncross-linking AGEs (adducts), as well as proteolytic enzymes known to play a role in aneurysm development (matrix metalloproteinase [MMP]-2, MMP-9, cathepsin B and S) were quantified. Ex vivo, nondiabetic AAA biopsies were glycated and measured subsequently for collagen type I release.

Results:

Pentosidine concentrations in AAA wall biopsies were increased in patients with diabetes compared with nondiabetics 9.4 (5.0-13.5) vs 6.0 (2.5-9.6) pmol/μmol lysine (P= .02). Increased pentosidine concentrations were also observed in nonaneurysmatic aortic wall biopsies from diabetic patients. In diabetic AAA vascular wall tissue, pentosidine concentration was negatively correlated with aortic diameter (r= −0.43;P= .02). Ex vivo glycated AAA biopsies were resistant against MMP-induced collagen type I degradation as compared with controls (7.0 vs 10.4 μg/L;P= .02). No differences were observed for AGEs that are not forming cross-links.

Conclusions:

These findings suggest that cross-linking AGEs like pentosidine play a protective role in AAA progression in diabetic patients.

Clinical Relevance:

Diabetes is negatively associated with progression of abdominal aortic aneurysm (AAA). We hypothesized that glycation of AAA tissue protects against proteolytic breakdown. Advanced glycation end products (AGEs) were measured in AAA biopsies (30 diabetics vs 30 nondiabetics). Higher levels of AGEs in diabetic AAA tissue were observed, and in vitro glycated AAA biopsies were more resistant against proteolysis. AGEs were correlated negatively with aortic diameter. These findings suggest that AGEs play a protective role in AAA progression. Metformin inhibits the formation of AGEs. Patients with diabetes and AAA disease might have decreased AAA progression if they switch to another oral antidiabetic or insulin.

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