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CLINICAL RESEARCH: ATHEROSCLEROSIS

Elevated Levels of VE-Cadherin-Positive Endothelial Microparticles in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

Hidenobu Koga, MD^_*, Seigo Sugiyama, MD, PhD^_*,_*, Kiyotaka Kugiyama, MD, PhD, Keisuke Watanabe, MD^_*, Hironobu Fukushima, MD^_*, Tomoko Tanaka, MD^_*, Tomohiro Sakamoto, MD, PhD^_*, Michihiro Yoshimura, MD, PhD^_*, Hideaki Jinnouchi, MD, PhD and Hisao Ogawa, MD, PhD^_*

^_* Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
2nd Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering University of Yamanashi, Yamanashi, Japan
Department of Jinnouchi Diabetes Center, Kumamoto, Japan

Manuscript received November 25, 2004; revised manuscript received January 19, 2005, accepted February 1, 2005.

^_* Reprint requests and correspondence: Dr. Seigo Sugiyama, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto, Japan 860-8556. (Email: ssugiyam{at}kumamoto-u.ac.jp).

OBJECTIVES: The purpose of this study was to examine whether CD144-EMP (endothelium-derived microparticles) is useful as a specific marker of endothelial cell (EC) dysfunction and to determine whether plasma levels of circulating CD144-EMP predicted coronary artery disease (CAD) in patients with type 2 diabetes mellitus (DM).

BACKGROUND: Endothelial cell dysfunction is involved in atherogenesis; however, the quantitative assessment of EC dysfunction has yet to be established clinically. Endothelium-derived microparticles are small, membrane-shed vesicles that are generated from the EC surface in response to cellular dysfunction and/or injury. Diabetes mellitus is known to be associated with EC dysfunction and accelerated atherosclerosis.

METHODS: We characterized EMP using anti-CD144 (VE-Cadherin) antibody in various atherosclerosis-related cells and investigated the association between the levels of CD144-positive microparticles and hydrogen-peroxide-induced EC injury and acetylcholine-induced coronary vasomotion. Furthermore, we evaluated plasma CD144-EMP levels in patients with and without DM.

RESULTS: We demonstrated that CD144-positive microparticles were derived selectively from human EC. The levels of CD144-EMP reflected the degree of in vitro hydrogen-peroxide-induced EC injury and impairment of in vivo endothelium-dependent coronary vasodilation (p < 0.01). Plasma CD144-EMP levels were increased significantly in DM patients compared with patients without DM (p < 0.001). In DM patients, the elevated levels of CD144-EMP were the most significant risk factor for CAD relative to all other traditional risk factors (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.8 to 6.9, p < 0.001). Notably, plasma CD144-EMP identified a subpopulation of established CAD patients in DM subjects without typical anginal symptoms (OR 10.6, 95% CI 3.9 to 29.5, p < 0.001).

CONCLUSIONS: The CD144-positive EMP exist in human plasma, and plasma CD144-EMP levels can be a clinically specific and quantitative marker of EC dysfunction and/or injury. Measurement of CD144-EMP, by providing a quantitative assessment of EC dysfunction, may be useful for identifying DM patients with increased risk of CAD.

Abbreviations and Acronyms   ACh = acetylcholine   CAD = coronary artery disease   CI = confidence interval   DM = diabetes mellitus   EC = endothelial cells   EMP = endothelium-derived microparticles   FCS = fetal calf serum   FITC = fluorescein isothiocyanate   HAoSMC = human aortic smooth muscle cells   HCAEC = human coronary artery endothelial cells   HDL = high-density lipoprotein   hs-CRP = high-sensitivity C-reactive protein   LAD = left anterior descending coronary artery   LDL = low-density lipoprotein   LMT = left main trunk coronary artery   OR = odds ratio   PBS = phosphate-buffered saline   sICAM-1 = soluble intercellular adhesion molecule-1

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