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J Am Coll Cardiol, 2005; 45:1622-1630, doi:10.1016/j.jacc.2005.02.047
© 2005 by the American College of Cardiology Foundation
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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{dagger}, Keisuke Watanabe, MD*, Hironobu Fukushima, MD*, Tomoko Tanaka, MD*, Tomohiro Sakamoto, MD, PhD*, Michihiro Yoshimura, MD, PhD*, Hideaki Jinnouchi, MD, PhD{ddagger} and Hisao Ogawa, MD, PhD*

* Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
{dagger} 2nd Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering University of Yamanashi, Yamanashi, Japan
{ddagger} 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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