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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:776.)
© 2007 American Heart Association, Inc.

Vascular Biology

Downregulation of Bone Morphogenetic Protein 4 Expression in Coronary Arterial Endothelial Cells

Role of Shear Stress and the cAMP/Protein Kinase A Pathway

Anna Csiszar; Nazar Labinskyy; Kira E. Smith; Aracelie Rivera; Erik N.T.P. Bakker; Hanjoong Jo; Jason Gardner; Zsuzsanna Orosz; Zoltan Ungvari

From the Department of Physiology (A.C., N.L., K.E.S., A.R., Z.O., Z.U.), New York Medical College, Valhalla; Department of Medical Physics (E.N.T.P.B.), Academic Medical Center, Amsterdam, The Netherlands; Wallace H. Coulter Department of Biomedical Engineering (H.J.), Georgia Institute of Technology and Emory University, Atlanta; and Department of Cell and Developmental Biology & Anatomy (J.G.), School of Medicine, University of South Carolina, Columbia.

Correspondence to Zoltan Ungvari, MD, PhD, Department of Physiology, New York Medical College, Valhalla, New York 10595. E-mail zoltan_ungvari{at}nymc.edu

Objective— Bone morphogenetic protein 4 (BMP-4) is a transforming growth factor ß family member cytokine that exerts proinflammatory effects on the endothelium and is likely to play a role in atherogenesis. Recent studies suggested that atheroprotective levels of shear stress control endothelial BMP-4 expression; however, the underlying mechanisms remained unknown.

Methods and Results— We found that shear stress downregulated BMP-4 expression in human and rat coronary arterial endothelial cells (CAECs) as well as in cultured mesenteric arterioles, although it had no effect on the expression of BMP-2, a related cytokine. In human coronary arterial endothelial cells, 8-bromo-cAMP, the adenylate cyclase activator forskolin, or a cAMP-dependent protein kinase (PKA) activator effectively decreased BMP-4 expression, mimicking the effects of shear stress. Indeed, shear stress induced the nuclear translocation of PKA-c, and inhibition of PKA attenuated the effects of shear stress and forskolin on BMP-4 expression. RNA decay assay and BMP-4 promoter-driven luciferase reporter gene assay showed that cAMP regulates BMP-4 expression at the transcriptional level.

Conclusions— Laminar shear stress and the cAMP/PKA pathway are important negative regulators of BMP-4 expression in the vascular endothelium. Because BMP-4 elicits endothelial activation and dysfunction, hypertension, and vascular calcification, inhibition of BMP-4 expression by shear stress and the cAMP/PKA pathway is likely to exert antiatherogenic and vasculoprotective effects.

Here we provide evidence that laminar shear stress and the cAMP/PKA pathway are important negative regulators of BMP-4 expression in the vascular endothelium. Because BMP-4 elicits endothelial activation and dysfunction, hypertension, and vascular calcification, inhibition of BMP-4 expression is likely to exert antiatherogenic and vasculoprotective effects.

Key Words: atherosclerosis • inflammation • atrioventricular fistula • hemodynamic forces • endothelium

This article has been cited by other articles:

				A. Csiszar, N. Labinskyy, H. Jo, P. Ballabh, and Z. Ungvari Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H569 - H577. [Abstract] [Full Text] [PDF]

				Z. I. Ungvari Endothelium-Derived Bone Morphogenic Protein Antagonists May Counteract the Proatherogenic Vascular Effects of Bone Morphogenic Protein 4 Circulation, September 11, 2007; 116(11): 1221 - 1223. [Full Text] [PDF]