Published online before print June 16, 2005, doi: 10.1161/01.RES.0000174286.73200.d4
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Submitted on May 11, 2004
Revised on June 3, 2005
Accepted on June 8, 2005
Overexpression of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Induces Intramyocardial Vasculopathy in Apolipoprotein E-Null Mice
Kazuhiko Inoue ;
From the Department of Vascular Physiology (K.I., Y.A., T.S.), National Cardiovascular Center Research Institute, Osaka; the Department of Cardiovascular Medicine (K.I., T.K.), Graduate School of Medicine, Kyoto University; the Department of Physiological Chemistry and Metabolism (H.K.), Graduate School of Medicine, University of Tokyo; and the Department of Molecular Pathophysiology (T.S.), Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
* To whom correspondence should be addressed. E-mail: t-sawamura{at}umin.ac.jp.
Endothelial dysfunction induced by oxidized low-density lipoprotein (OxLDL) has been implicated in the pathogenesis of atherosclerosis and vasculopathy. Increased expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the receptor for OxLDL in endothelial cells, has been demonstrated in the atherosclerotic plaques from experimental atherosclerotic animal models and human clinical samples. In vitro, activation of LOX-1 alters the expression of several endothelial cell genes that are involved in endothelial dysfunction. To investigate the role of LOX-1 in terms of both endothelial dysfunction and resultant vascular changes, we generated mice overexpressing LOX-1 (LOXtg) in C57BL/6 and apolipoprotein E-null mice (apoEKO) backgrounds. We found that the expression of the transgene was prominent in coronary vessels and cardiomyocytes. The enhancement of OxLDL uptake in LOXtg mice was consistent with the expression level of LOX-1. Under hyperlipidemic conditions, both OxLDL and 8-hydroxy-2'-deoxyguanosine accumulated in the coronary arteries of LOXtg/apoEKO mice. The expression of ICAM-1 and VCAM-1, as well as the number of macrophages around blood vessels, were significantly increased in LOXtg/apoEKO mice compared with control littermates. There were no differences in either the hemodynamic profile or the plasma lipid profile between the 2 groups of animals. LOXtg/apoEKO mice displayed accelerated intramyocardial vasculopathy, and the atheroma-like lesion area was increased 10-fold in the LOXtg/apoEKO mice compared with nontransgenic littermates after 3-weeks on the high-fat diet. Thus, it is demonstrated that LOX-1 overexpression promotes inflammatory intramyocardial vasculopathy in a hyperlipidemic mouse model, and this effect is probably mediated through the endothelial dysfunction induced by overexpression of LOX-1.
Key words: endothelial dysfunction • lectin-like oxidized low-density lipoprotein receptor-1 • oxidized low-density lipoprotein
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