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(Circulation Research. 2009;105:575.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Heat Shock Protein 70 Enhances Vascular Bone Morphogenetic Protein-4 Signaling by Binding Matrix Gla Protein

Yucheng Yao, Andrew D. Watson, Sheng Ji, Kristina I. Boström

From the Division of Cardiology (Y.Y., A.D.W., S.J., K.I.B.), David Geffen School of Medicine; and Molecular Biology Institute (K.I.B.), University of California, Los Angeles.

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

Rationale: Matrix Gla protein (MGP) is a calcification inhibitor, which binds and inhibits bone morphogenetic protein (BMP)-2 and -4.

Objective: The objective was to determine whether MGP also binds other proteins, which could interfere with its function.

Methods and Results: We transfected bovine aortic endothelial cells with N-terminally FLAG-tagged MGP and used immunoprecipitation and liquid chromatographic–tandem mass spectrometric analysis to identify MGP-binding proteins. Heat shock protein (HSP)70, a stress-induced protein expressed in atherosclerotic lesions and soluble in serum, was identified as a novel MGP-binding protein. The interaction between MGP and HSP70 was confirmed by coimmunoprecipitation and chemical crosslinking, and blocked the interaction between MGP and BMP-4. In endothelial cells, HSP70 enhanced BMP-4–induced proliferation and tube formation, and in calcifying vascular cells, HSP70 enhanced BMP-induced calcium deposition. In addition, HSP70 mediated the procalcific effect of interleukin-6 on calcifying vascular cells. In apolipoprotein E–null mice, a model for atherosclerosis, levels of BMP-4, HSP70, MGP, and interleukin-6 were elevated in the aortic wall. Levels of BMP-4, HSP70, and interleukin-6 were also elevated in serum, and anti-HSP70 antibodies diminished its procalcific effect on calcifying vascular cells.

Conclusion: HSP70 binds MGP and enhances BMP activity, thereby functioning as a potential link between cellular stress, inflammation, and BMP signaling.

Key Words: heat shock protein 70 • matrix Gla protein • bone morphogenetic protein • protein interaction