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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2266.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

High-Density Lipoproteins Affect Endothelial BMP-Signaling by Modulating Expression of the Activin-Like Kinase Receptor 1 and 2

Yucheng Yao; Esther S. Shao; Medet Jumabay; Ani Shahbazian; Sheng Ji; Kristina I. Boström

From the Division of Cardiology, David Geffen School of Medicine (Y.Y., E.S.S., M.J., A.S., S.J., K.I.B.), and the Molecular Biology Institute (K.I.B.), UCLA, Los Angeles, Calif.

Correspondence to Kristina I. Boström, MD, PhD, Division of Cardiology, David Geffen School of Medicine at UCLA, Box 951679, Los Angeles, CA 90095-1679. E-mail kbostrom{at}mednet.ucla.edu

Objective— High-density lipoproteins (HDL) have antiinflammatory effects on the vascular endothelium. Because bone morphogenetic proteins (BMPs) are known to be inflammatory mediators, we examined the effect of HDL on BMP signaling.

Methods and Results— Increasing concentrations of HDL progressively enhanced expression of the activin-like kinase receptor (ALK)1 and ALK2 in human aortic endothelial cells as determined by real-time polymerase chain reaction and immunoblotting. Induction of ALK1 was a result of enhanced ALK2 expression as determined by siRNA interference, and was associated with increased levels of vascular endothelial growth factor (VEGF) and matrix Gla protein (MGP). The HDL-induction of ALK2 was dependent on BMP-signaling, and affected coregulation of the ALK2 gene by the homeodomain proteins MSX2, DLX3, and DLX5, as determined by reporter gene assays, siRNA interference, and chromatin immunoprecipitation. Apolipoprotein A-I transgenic mice, known to have high HDL and inhibition of atherogenesis, exhibited similar changes in aortic gene expression as seen in endothelial cells treated with HDL in vitro.

Conclusions— We conclude that HDL benefits the arterial wall by allowing for enhanced ALK1 and ALK2 signaling, resulting in an increase of VEGF and MGP, essential for endothelial cell survival and prevention of vascular calcification, respectively.

High-density proteins (HDL) affect signaling by bone morphogenetic proteins (BMP), inflammatory mediators in endothelial cells. HDL promotes expression of the activin-like kinase receptor (ALK)2, a BMP-receptor, which stimulates ALK1 expression and allows for increased expression of VEGF and matrix Gla protein, thereby promoting vascular health.

Key Words: high-density lipoproteins • bone morphogenetic proteins • BMP-receptors • endothelial cells • homeodomain proteins