Research Paper

Calcification of the Medial Layer of the Internal Thoracic Artery in Diabetic Patients: Relevance of Glycoxidation
Noriyuki Sakata^a, Kazuma Takeuchi^b, Keita Noda^b, Keijiro Saku^b, Yutaka Tachikawa^c, Tadashi Tashiro^c, Ryoji Nagai^d, Seikoh Horiuchi<sup>d

a</sup>Department of Pathology,
^bSecond Department of Internal Medicine,
^cDepartment of Cardiovascular Surgery, School of Medicine, Fukuoka University, Fukuoka,
^dDepartment of Biochemistry, Kumamoto University School of Medicine, Kumamoto, Japan

Address of Corresponding Author

J Vasc Res 2003;40:567-574 (DOI: 10.1159/000075807)

  Key Words

• Calcification
• Diabetes mellitus
• N-(carboxymethyl)lysine
• Internal thoracic artery
• Chemically modified collagen

  Abstract

Objective: The aim of this study was to evaluate the role of glycoxidation in the calcification of the internal thoracic artery (ITA) in diabetes mellitus (DM). Methods: ITA samples were obtained from 17 patients with type 2 DM (age 62.9 ± 10.5 years) and 12 age-matched, nondiabetic patients (age 62.5 ± 10.2 years) who underwent coronary artery bypass grafting. These samples were analyzed histopathologically and assessed for calcification by von Kossa staining and for glycoxidation by immunohistochemistry using anti-N-(carboxymethyl)lysine (CML) antibody. Morphometric evaluation of calcification of the medial layer, intimal thickness and intima-to-media ratio was performed using NIH image software. To evaluate the mechanism of the interaction between calcification and glycoxidation, we developed an in vitro model of calcification of collagen that was chemically modified by glucose, glutaraldehyde or epoxy compound. The calcium-binding activity of these collagens was determined in hydrolysates using atomic absorption spectrophotometry. Results: ITAs of both diabetic and nondiabetic patients were free of atherosclerosis, and no differences were found between the two groups with regard to intimal thickness and intima-to-media ratio. Areas of calcification were noticed in both groups in the tunica media, but not in the tunica intima. Calcium deposits were localized within the extracellular matrix, which was immunohistochemically positive for CML. The extent of medial layer calcification was significantly greater in diabetic patients than nondiabetic subjects, but was independent of known risk factors such as hypertension, hyperlipidemia, obesity and history of old myocardial infarction. The binding activity of collagen was time-dependently increased with in vitro incubation of glucose. A significant increase in the calcium-binding ability was observed in glucose- and glutaraldehyde-modified collagens, but not in epoxy compound-modified collagen. Conclusion: Our results suggest that glycoxidative modification of the extracellular matrix, in particular collagen, of the vascular wall may enhance the development of ITA calcification in diabetic patients.

Copyright © 2003 S. Karger AG, Basel

  Author Contacts

Dr. Noriyuki Sakata
Department of Pathology, School of Medicine, Fukuoka University
45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka 814-0180 (Japan)
Tel. +81 92 801 1011, ext. 3281, Fax +81 92 863 8383
E-Mail nysakata@fukuoka-u.ac.jp

  Article Information

Received: July 2, 2003
Accepted after revision: November 10, 2003
Published online: December 23, 2003
Number of Print Pages : 8
Number of Figures : 6, Number of Tables : 2, Number of References : 30