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Journal of Lipid Research, Vol. 44, 539-546, March 2003
Copyright © 2003 by Lipid Research, Inc.

Apolipoprotein composition and particle size affect HDL degradation by chymase

Miriam Lee^*,**, Petri T. Kovanen^1,*, Gabriella Tedeschi, Emanuela Oungre, Guido Franceschini and Laura Calabresi

^* Wihuri Research Institute, Helsinki, Finland
Center E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milan, Italy
Institute of Veterinary Physiology and Biochemistry, University of Milan, Italy
^** Faculty of Biology, University of Havana, Cuba

¹ To whom correspondence should be addressed. e-mail: petri.kovanen{at}wri.fi

Mast cell chymase, a chymotrypsin-like neutral protease, can proteolyze HDL₃. Here we studied the ability of rat and human chymase to proteolyze discoidal preß-migrating reconstituted HDL particles (rHDLs) containing either apolipoprotein A-I (apoA-I) or apoA-II. Both chymases cleaved apoA-I in rHDL at identical sites, either at the N-terminus (Tyr¹⁸ or Phe³³) or at the C-terminus (Phe²²⁵), so generating three major truncated polypeptides that remained bound to the rHDL. The cleavage sites were independent of the size of the rHDL particles, but small particles were more susceptible to degradation than bigger ones. Chymase-induced truncation of apoA-I yielded functionally compromised rHDL with reduced ability to promote cellular cholesterol efflux. In sharp contrast to apoA-I, apoA-II was resistant to degradation. However, when apoA-II was present in rHDL that also contained apoA-I, it was degraded by chymase.

We conclude that chymase reduces the ability of apoA-I in discoidal rHDL particles to induce cholesterol efflux by cleaving off either its amino- or carboxy-terminal portion. This observation supports the concept that limited extracellular proteolysis of apoA-I is one pathophysiologic mechanism leading to the generation and maintenance of foam cells in atherosclerotic lesions.

Abbreviations: rHDL, reconstituted HDL; rh-chymase, recombinant human chymase

Supplementary key words apoA-I proteolysis • mast cell chymase • reconstituted HDL

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