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J. Biol. Chem., Vol. 278, Issue 33, 31128-31135, August 15, 2003
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From the
Wallace H. Coulter Department of
Biomedical Engineering at Georgia Tech and Emory University and the
Division of Cardiology and
¶Department of Surgery, Emory University,
Atlanta, Georgia 30322
Atherosclerosis is now viewed as an inflammatory disease occurring
preferentially in arterial regions exposed to disturbed flow conditions,
including oscillatory shear stress (OS), in branched arteries. In contrast,
the arterial regions exposed to laminar shear (LS) are relatively lesion-free.
The mechanisms underlying the opposite effects of OS and LS on the
inflammatory and atherogenic processes are not clearly understood. Here,
through DNA microarrays, protein expression, and functional studies, we
identify bone morphogenic protein 4 (BMP4) as a mechanosensitive and
pro-inflammatory gene product. Exposing endothelial cells to OS increased BMP4
protein expression, whereas LS decreased it. In addition, we found BMP4
expression only in the selective patches of endothelial cells overlying foam
cell lesions in human coronary arteries. The same endothelial patches also
expressed higher levels of intercellular cell adhesion molecule-1 (ICAM-1)
protein compared with those of non-diseased areas. Functionally, we show that
OS and BMP4 induced ICAM-1 expression and monocyte adhesion by a
NF
B-dependent mechanism. We suggest that BMP4 is a mechanosensitive,
inflammatory factor playing a critical role in early steps of atherogenesis in
the lesion-prone areas.
Received for publication, January 21, 2003 , and in revised form, May 22, 2003.
* This work was supported by Grants HL71014, HL67413, and HL70531 from the National Institute of Health (to H. J. and W. R. T.), NASA (NAG2-1431), and the Whitaker Foundation (H. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| To whom correspondence should be addressed: Wallace H. Coulter Dept. of Biomedical Engineering at Georgia Tech and Emory University, Atlanta, GA 30322. Tel.: 404-712-9654; Fax: 404-727-3330; E-mail: hanjoong.jo{at}bme.gatech.edu.
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