J. Lipid Res. Acyl Labeled PIP's available August 1, 2008
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Originally published In Press as doi:10.1194/jlr.M700392-JLR200 on November 8, 2007

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Journal of Lipid Research, Vol. 49, 358-368, February 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Association of cholesteryl ester transfer protein with HDL particles reduces its proteolytic inactivation by mast cell chymase

Miriam Lee-Rueckert1,*, Riikka Vikstedt1,{dagger}, Jari Metso{dagger}, Matti Jauhiainen{dagger} and Petri T. Kovanen2,*

* Wihuri Research Institute, Helsinki, Finland
{dagger} National Public Health Institute, Department of Molecular Medicine, Biomedicum, Helsinki, Finland

Published, JLR Papers in Press, November 8, 2007.

1 M. Lee-Rueckert and R. Vikstedt contributed equally to this work.

2 To whom correspondence should be addressed. e-mail: petri.kovanen{at}wri.fi

Human atherosclerotic intima contains mast cells that secrete the neutral protease chymase into the intimal fluid, which also contains HDL-modifying proteins, such as cholesteryl ester transfer protein (CETP), in addition to abundant amounts of nascent discoidal HDL particles. Here, we studied chymase-dependent degradation of a) CETP isolated from human plasma and b) CETP-HDL complexes as well as the functional consequences of such degradations. Incubation with chymase caused a rapid cleavage of CETP, yielding a specific proteolytic pattern with a concomitant reduction in its cholesteryl ester transfer activity. These chymase-dependent effects were attenuated after CETP was complexed with HDL. This attenuation was more effective when CETP was complexed with HDL3 and HDL2 than with discoidal reconstituted high density lipoprotein (rHDL). Conversely, rHDL, but not spherical HDLs, was protected in such CETP complexes against functional inactivation by chymase. Thus, in contrast to the complexes of CETP with spherical HDLs, the ability of the CETP-rHDL complexes to promote cholesterol efflux from macrophage foam cells remained unchanged, despite treatment with chymase. In summary, complexation of CETP and HDL modifies their resistance to proteolytic inactivation: spherical HDLs protect CETP, and CETP protects discoidal HDL. These results suggest that in inflamed atherosclerotic intima, CETP, via its complexation with HDL, has a novel protective role in early steps of reverse cholesterol transport.

Supplementary key words proteolysis • cholesterol efflux • reverse cholesterol transport • high density lipoprotein


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