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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
- Source :
- Arteriosclerosis, thrombosis, and vascular biology. 36(6)
- Publication Year :
- 2015
-
Abstract
- Objective— 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). Approach and Results— 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. Conclusions— 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.
- Subjects :
- 0301 basic medicine
Vascular smooth muscle
Myocytes, Smooth Muscle
Receptor for Advanced Glycation End Products
030204 cardiovascular system & hematology
Endocytosis
Calcium in biology
Muscle, Smooth, Vascular
Article
Wortmannin
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Animals
Humans
Trypsin
Protein Kinase Inhibitors
Cells, Cultured
Foam cell
Phosphoinositide-3 Kinase Inhibitors
Mice, Knockout
Pinocytosis
Acetylation
Biological Transport
Receptor-mediated endocytosis
Sterol Esterase
musculoskeletal system
Atherosclerosis
Calcium Channel Blockers
Scavenger Receptors, Class E
Cell biology
Lipoproteins, LDL
030104 developmental biology
chemistry
Low-density lipoprotein
cardiovascular system
Macrophages, Peritoneal
Calcium
Phosphatidylinositol 3-Kinase
Cardiology and Cardiovascular Medicine
Reactive Oxygen Species
Foam Cells
Subjects
Details
- ISSN :
- 15244636
- Volume :
- 36
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Accession number :
- edsair.doi.dedup.....73ad33c961611cc94758e45ac15c735e