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(Circulation. 2007;116:1258-1266.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Bone Morphogenic Protein Antagonists Are Coexpressed With Bone Morphogenic Protein 4 in Endothelial Cells Exposed to Unstable Flow In Vitro in Mouse Aortas and in Human Coronary Arteries

Role of Bone Morphogenic Protein Antagonists in Inflammation and Atherosclerosis

Kyunghwa Chang, PhD; Daiana Weiss, MD; Jin Suo, PhD; J. David Vega, MD; Don Giddens, PhD; W. Robert Taylor, MD, PhD; Hanjoong Jo, PhD

From the Wallace H. Coulter Department of Biomedical Engineering (K.C., J.S., D.G., W.R.T., H.J.), Georgia Institute of Technology and Emory University, Atlanta, Ga, and the Department of Surgery (J.D.V.), and Division of Cardiology (D.W., W.R.T., H.J.), Emory University, Atlanta, Ga.

Correspondence to Hanjoong Jo, PhD, Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, 2005 WMB, Atlanta, GA 30322. E-mail hanjoong.jo{at}bme.gatech.edu

Received December 11, 2006; accepted June 29, 2007.

Background— Exposure to disturbed flow, including oscillatory shear stress, stimulates endothelial cells (ECs) to produce bone morphogenic protein (BMP) 4, which in turn activates inflammation, a critical atherogenic step. BMP activity is regulated by the level of BMP antagonists. Until now it was not known whether shear also regulates the expression of BMP antagonists and whether they play a role in EC pathophysiology.

Methods and Results— BMP antagonists follistatin, noggin, and matrix Gla protein were expressed in cultured bovine and human arterial ECs. Surprisingly, oscillatory shear stress increased expression of the BMP antagonists in ECs, whereas unidirectional laminar shear decreased such expression. Immunohistochemical studies with mouse aortas showed data consistent with in vitro findings: Only ECs in the lesser curvature exposed to disturbed flow, but not those in the greater curvature and straight arterial regions exposed to undisturbed flow, showed coexpression of BMP4 and the BMP antagonists. Similarly, in human coronary arteries, expression of BMP4 and BMP antagonists in ECs positively correlated with the severity of atherosclerosis. Monocyte adhesion induced by oscillatory shear stress was inhibited by knockdown of BMP4 or treatment with recombinant follistatin or noggin, whereas it was increased by knockdown of follistatin and/or noggin.

Conclusions— The present results suggest that ECs coexpress BMP antagonists along with BMP4 in an attempt to minimize the inflammatory response by oscillatory shear stress as part of a negative feedback mechanism. The balance between the agonist, BMP4, and its antagonists may play an important role in the overall control of inflammation and atherosclerosis.

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