A macrophage sterol-responsive network linked to atherogenesis.
Cholesteryl ester accumulation by macrophages is a critical early event in atherogenesis. To test the hypothesis that sterol loading promotes foam cell formation and vascular disease by perturbing a network of interacting proteins, we used a global approach to identify proteins that are differentially expressed when macrophages are loaded with cholesterol in vivo. Our analysis revealed a sterol-responsive network that is highly enriched in proteins with known physical interactions, established roles in vesicular transport, and demonstrated atherosclerotic phenotypes in mice. Pharmacologic intervention with a statin or rosiglitazone and use of mice deficient in LDL receptor or apolipoprotein E implicated the network in atherosclerosis. Biochemical fractionation revealed that most of the sterol-responsive proteins resided in microvesicles, providing a physical basis for the network's functional and biochemical properties. These observations identify a highly integrated network of proteins whose expression is influenced by environmental, genetic, and pharmacological factors implicated in atherogenesis.
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Lev
L
Becker
Sina A
SA
Gharib
Angela D
AD
Irwin
Ellen
E
Wijsman
Tomas
T
Vaisar
John F
JF
Oram
Jay W
JW
Heinecke
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D019821:Simvastatin / Q000494:pharmacology; D013261:Sterols / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology
D001057:Apolipoproteins E; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D011506:Proteins; D011973:Receptors, LDL; D013261:Sterols; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019821:Simvastatin