Mast cell activation in vivo impairs the macrophage reverse cholesterol transport pathway in the mouse

Miriam Lee-Rueckert, Reija Silvennoinen, Noemi Rotllan, Ilona Judström, Francisco Blanco-Vaca, Jari Metso, Matti Jauhiainen, Petri T. Kovanen, Joan Carles Escola-Gil

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17 Citations (Scopus)

Abstract

Objective-: Chymase released by activated mast cells degrades high-density lipoproteins. We evaluated whether local activation of mast cells would attenuate cholesterol efflux from neighboring macrophage foam cells, thereby disrupting the entire in vivo pathway of macrophage-specific reverse cholesterol transport (RCT). Methods and Results-: C57Bl/6J mice received intraperitoneal injections of the mast cell-degranulating compound 48/80 to induce peritoneal mast cell activation, human apolipoprotein A-I (apoA-I) to stimulate RCT, and [H]cholesterol-labeled J774 macrophages for measurement of the rate of RCT. After 3 hours, H-radioactivity was measured in the intestinal lumen contents. Activation of mast cells in the peritoneal cavity depleted human apoA-I pre-β-migrating species, impairing the ability of the peritoneal fluid to efficiently promote cholesterol efflux from cultured macrophages. Moreover, intact but not chymase-treated (proteolyzed) apoA-I accelerated the transfer of macrophage-derived H- radioactivity to the intestinal contents. Importantly, stimulation of RCT by human apoA-I was fully blocked by 48/80 in mast cell-competent wild-type C57Bl/6J mice but not in mast cell-deficient W-sashc-kit mutant mice. The ability of intraperitoneally administered phospholipid vesicles to promote RCT in wild-type mice was not blocked by 48/80, supporting the notion that mast cell-dependent proteolysis of the intraperitoneally administered apoA-I was responsible for RCT inhibition. Conclusion-: Overall, our results suggest that tissue-specific activation of mast cells with ensuing release of chymase is able to proteolytically inactivate apoA-I in the microenvironment of the activated mast cells, thus locally impairing the initiation of macrophage RCT in vivo. Copyright © 2011 American Heart Association. All rights reserved.
Original languageEnglish
Pages (from-to)520-527
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number3
DOIs
Publication statusPublished - 1 Mar 2011

Keywords

  • apolipoprotein A-I
  • cholesterol efflux
  • macrophages
  • mast cell chymase
  • reverse cholesterol transport

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