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



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.



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.



These findings suggest that cross-linking AGEs like pentosidine play a protective role in AAA progression in diabetic patients.
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands; Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: d_koole@yahoo.com.
Dave
D
Koole
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
Joost A
JA
van Herwaarden
Department of Internal Medicine, Laboratory for Metabolism and Vascular Medicine, Maastricht University, Maastricht, The Netherlands.
Casper G
CG
Schalkwijk
Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Floris P J G
FPJG
Lafeber
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Aryan
A
Vink
Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
Mirjam B
MB
Smeets
Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Gerard
G
Pasterkamp
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
Frans L
FL
Moll
D000368:Aged; D001012:Aorta, Abdominal / Q000737:chemistry* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism* / Q000473:pathology; D001120:Arginine / Q000031:analogs & derivatives / Q000032:analysis; D016022:Case-Control Studies; D002403:Cathepsins / Q000032:analysis; D024042:Collagen Type I / Q000032:analysis*; D016207:Cytokines / Q000032:analysis; D003920:Diabetes Mellitus / Q000378:metabolism*; D005260:Female; D017127:Glycation End Products, Advanced / Q000032:analysis*; D006031:Glycosylation; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000032:analysis; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis; D055550:Protein Stability; D059748:Proteolysis
D024042:Collagen Type I; D016207:Cytokines; D017127:Glycation End Products, Advanced; D001120:Arginine; C062187:pentosidine; D002403:Cathepsins; D020782:Matrix Metalloproteinases; D008239:Lysine