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Circ Res. 2009 Sep 11;105(6):575-84. doi: 10.1161/CIRCRESAHA.109.202333. Epub 2009 Aug 6.

Heat shock protein 70 enhances vascular bone morphogenetic protein-4 signaling by binding matrix Gla protein.

Author information

1
Division of Cardiology, David Geffen School of Medicine at UCLA, Box 951679, Los Angeles, CA 90095-1679, USA.

Abstract

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.

PMID:
19661459
PMCID:
PMC2779117
DOI:
10.1161/CIRCRESAHA.109.202333
[Indexed for MEDLINE]
Free PMC Article

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