title: Enzymatically Modified Low-Density Lipoprotein Promotes Foam Cell Formation in Smooth Muscle Cells via Macropinocytosis and Enhances Receptor-Mediated Uptake of Oxidized Low-Density Lipoprotein.
abstract: Enzyme-modified nonoxidized low-density lipoprotein (ELDL) is present in human atherosclerotic lesions. Our objective is to understand the mechanisms of ELDL uptake and its effects on vascular smooth muscle cells (SMC).
  
  
  
  Transformation of murine aortic SMCs into foam cells in response to ELDL was analyzed. ELDL, but not acetylated or oxidized LDL, was potent in inducing SMC foam cell formation. Inhibitors of macropinocytosis (LY294002, wortmannin, amiloride) attenuated ELDL uptake. In contrast, inhibitors of receptor-mediated endocytosis (dynasore, sucrose) and inhibitor of caveolae-/lipid raft-mediated endocytosis (filipin) had no effect on ELDL uptake in SMC, suggesting that macropinocytosis is the main mechanism of ELDL uptake by SMC. Receptor for advanced glycation end products (RAGE) is not obligatory for ELDL-induced SMC foam cell formation, but primes SMC for the uptake of oxidized LDL in a RAGE-dependent manner. ELDL increased intracellular reactive oxygen species, cytosolic calcium, and expression of lectin-like oxidized LDL receptor-1 in wild-type SMC but not in RAGE(-/-) SMC. The macropinocytotic uptake of ELDL is regulated predominantly by intracellular calcium because ELDL uptake was completely inhibited by pretreatment with the calcium channel inhibitor lacidipine in wild-type and RAGE(-/-) SMC. This is in contrast to pretreatment with PI3 kinase inhibitors which completely prevented ELDL uptake in RAGE(-/-) SMC, but only partially in wild-type SMC.
  
  
  
  ELDL is highly potent in inducing foam cells in murine SMC. ELDL endocytosis is mediated by calcium-dependent macropinocytosis. Priming SMC with ELDL enhances the uptake of oxidized LDL.
authors.affiliation: From the Department of Medicine (B.C., M.A.H.B.), and Department of Pathology (C.A.R., G.S.G), University of Chicago, IL. bchellan@bsd.uchicago.edu mhofmann@medicine.bsd.uchicago.edu.
authors.forename: Bijoy
authors.initials: B
authors.lastname: Chellan
authors.affiliation: From the Department of Medicine (B.C., M.A.H.B.), and Department of Pathology (C.A.R., G.S.G), University of Chicago, IL.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Reardon
authors.affiliation: From the Department of Medicine (B.C., M.A.H.B.), and Department of Pathology (C.A.R., G.S.G), University of Chicago, IL.
authors.forename: Godfrey S
authors.initials: GS
authors.lastname: Getz
authors.affiliation: From the Department of Medicine (B.C., M.A.H.B.), and Department of Pathology (C.A.R., G.S.G), University of Chicago, IL. bchellan@bsd.uchicago.edu mhofmann@medicine.bsd.uchicago.edu.
authors.forename: Marion A
authors.initials: MA
authors.lastname: Hofmann Bowman
mesh_terms: D000107:Acetylation; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010873:Pinocytosis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D002787:Sterol Esterase / Q000378:metabolism*; D014357:Trypsin / Q000378:metabolism*
chemical_list: C000593873:Ager protein, mouse; D002121:Calcium Channel Blockers; D008077:Lipoproteins, LDL; C495138:Olr1 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D058539:Phosphatidylinositol 3-Kinase; D002787:Sterol Esterase; D014357:Trypsin; D002118:Calcium
keywords: amiloride; atherosclerosis; endocytosis; foam cells; wortmannin