on March 20, 2003
Published online before print March 20, 2003, doi: 10.1161/01.ATV.0000067427.40133.59
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Submitted on January 27, 2003
Accepted on March 3, 2003
E-Selectin Polymorphism Associated With Myocardial Infarction Causes Enhanced Leukocyte-Endothelial Interactions Under Flow Conditions
Masayuki Yoshida *;
From the Department of Vascular Medicine and Medical Biochemistry (M.Y., Y.T.), Graduate School of Medicine, Tokyo Medical and Dental University; Department of Cardiology (T.S., T.I.), Kitasato University School of Medicine; and Department of Molecular Pathogenesis (A.K.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
* To whom correspondence should be addressed. E-mail: masa.vasc{at}tmd.ac.jp.
Objective--Polymorphisms found in genes encoding adhesion molecules have been reported to be associated with atherosclerosis. We investigated the Ser128Arg polymorphism in the E-selectin gene in Japanese patients with myocardial infarction and its functional significance.
Methods and Results--Results from 135 patients with myocardial infarction and 327 control subjects revealed that the frequency of Arg128-positive was significantly higher in the patients than in controls (12.6% versus 6.7%; odds ratio, 2.0; 95% CI, 1.04 to 3.85), indicating that the Ser128Arg polymorphism was associated with myocardial infarction. We then generated a recombinant E-selectin adenovirus carrying a mutation (AdS128R-E) and compared it with its wild-type counterpart by evaluating the adhesion characteristics of transduced human umbilical vein endothelial cells under flow. AdS128R-E-transduced human umbilical vein endothelial cells supported significantly more rolling and adhesion of neutrophils and mononuclear cells compared with human umbilical vein endothelial cells transduced with AdWT-E (P<0.001) and also exhibited significantly greater levels of phosphorylation of extracellular signal regulated kinase 1 and 2 and p38 mitogen-activated protein kinase, suggesting that an altered endothelial signaling pathway is associated with this polymorphism.
Conclusions--Our results suggest that the E-selectin Ser128Arg polymorphism can functionally alter leukocyte-endothelial interactions as well as biochemical and biological consequences, which may account for the pathogenesis of myocardial infarction.
Key words: E-selectin • polymorphism • endothelium • leukocyte adhesion • mitogen-activated protein kinase
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