Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease.
OBJECTIVE
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.
Koga
Hidenobu
H
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Sugiyama
Seigo
S
Kugiyama
Kiyotaka
K
Watanabe
Keisuke
K
Fukushima
Hironobu
H
Tanaka
Tomoko
T
Sakamoto
Tomohiro
T
Yoshimura
Michihiro
M
Jinnouchi
Hideaki
H
Ogawa
Hisao
H
D000368:Aged; D015703:Antigens, CD / Q000097:blood*; D015820:Cadherins / Q000097:blood*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood* / Q000175:diagnosis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis; D003925:Diabetic Angiopathies / Q000097:blood* / Q000175:diagnosis; D042241:Early Diagnosis; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D010316:Particle Size; D011237:Predictive Value of Tests; D012016:Reference Values; D012307:Risk Factors; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D018799:Intercellular Adhesion Molecule-1; D000099152:Cadherin 5