First Author | Lee-Rueckert M | Year | 2011 |
Journal | Arterioscler Thromb Vasc Biol | Volume | 31 |
Issue | 3 | Pages | 520-7 |
PubMed ID | 21212401 | Mgi Jnum | J:184173 |
Mgi Id | MGI:5320385 | Doi | 10.1161/ATVBAHA.110.221069 |
Citation | Lee-Rueckert M, et al. (2011) Mast cell activation in vivo impairs the macrophage reverse cholesterol transport pathway in the mouse. Arterioscler Thromb Vasc Biol 31(3):520-7 |
abstractText | 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 [(3)H]cholesterol-labeled J774 macrophages for measurement of the rate of RCT. After 3 hours, (3)H-radioactivity was measured in the intestinal lumen contents. Activation of mast cells in the peritoneal cavity depleted human apoA-I pre-beta-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 (3)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-sash c-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. CONCLUSIONS: 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. |