Association of cholesteryl ester transfer protein with HDL particles reduces its proteolytic inactivation by mast cell chymase.
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 HDL(3) and HDL(2) 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.
Lee-Rueckert
Miriam
M
Wihuri Research Institute, Helsinki, Finland.
Vikstedt
Riikka
R
Metso
Jari
J
Jauhiainen
Matti
M
Kovanen
Petri T
PT
D001693:Biological Transport, Active / Q000502:physiology; D045744:Cell Line, Tumor; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D008076:Cholesterol, HDL / Q000378:metabolism; D053818:Chymases / Q000502:physiology*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008407:Mast Cells / Q000201:enzymology*; D010316:Particle Size
C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D053818:Chymases