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Papers In Press, published online ahead of print December 16, 2002
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Wihuri Research Institute, Helsinki FIN-00140
Corresponding Author: petri.kovanen{at}wri.fi
Chymase, a chymotrypsin-like neutral protease secreted by stimulated mast cells, can proteolyze plasma HDL3. Here this effect was mimicked in a model system involving chymase from rat and human origin, and HDL particles of defined composition. Thus, discoidal prebeta-migrating reconstituted HDL particles (rHDLs) containing either apoA-I or apoA-II were incubated with the chymases, and the ability of the proteolyzed particles to promote cholesterol efflux from macrophage foam cells was then studied. The two chymases both proteolyzed apoA-I in rHDL at identical cleavage sites, either at the N-terminus (Tyr18 or Phe33) or at the C-terminus (Phe225), so generating three major truncated polypeptides which remained bound to the rHDL. The cleavage sites were independent of the rHDL particles size, but the smallest particles were more susceptible to chymase degradation than the bigger ones. Such truncation of the apoA-I yielded functionally compromised rHDL with reduced ability to promote efflux of cellular cholesterol. In sharp contrast to apoA-I, apoA-II was resistant to degradation, and its ability to promote cholesterol efflux was not influenced by chymase treatment. However, when apoA-II was present in rHDL which also contained apoA-I, it was degraded by chymase. We conclude that mast cell chymase reduces the ability of lipidated apoA-I in discoidal rHDL particles to induce cholesterol efflux from macrophage foam cells by cleaving off either the amino- or carboxy-terminal portion of this apolipoprotein. This observation provides support for the more general concept that limited extracellular proteolysis of apoA-I is one pathophysiologic mechanism leading to the generation and maintenance of foam cells in atherosclerotic lesions.
Revised on December 4, 2002
Accepted on December 9, 2002
Apolipoprotein composition and particle size affect HDL degradation by chymase: Effect on cellular cholesterol efflux
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