title: p38 mitogen-activated protein kinase (MAPK) promotes cholesterol ester accumulation in macrophages through inhibition of macroautophagy.
abstract: p38 MAPK has been strongly implicated in the development of atherosclerosis, but its role in cholesterol ester accumulation in macrophages and formation of foam cells, an early step in the development of atherosclerosis, has not been investigated. We addressed this issue and made some brand new observations. First, elevated intracellular cholesterol level induced by the exposure to LDL-activated p38 MAPK and activation of p38 MAPK with anisomycin increased the ratio of cholesterol esters over free cholesterol, whereas inhibition of p38 MAPK with SB203580 or siRNA reduced the LDL loading-induced intracellular accumulation of free cholesterol and cholesterol esters in macrophages. Second, exposure to LDL cholesterol inhibited autophagy in macrophages, and inhibition of autophagy with 3-methyladenine increased intracellular accumulation of cholesterol (free cholesterol and cholesterol esters), whereas activation of autophagy with rapamycin decreased intracellular accumulation of free cholesterol and cholesterol esters induced by the exposure to LDL cholesterol. Third, LDL cholesterol loading-induced inhibition of autophagy was prevented by blockade of p38 MAPK with SB203580 or siRNA. Neutral cholesterol ester hydrolase was co-localized with autophagosomes. Finally, LDL cholesterol loading and p38 activation suppressed expression of the key autophagy gene, ulk1, in macrophages. Together, our results provide brand new insight about cholesterol ester accumulation in macrophages and foam cell formation.
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina 27559, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Mei
authors.forename: Haihua
authors.initials: H
authors.lastname: Gu
authors.forename: Adam
authors.initials: A
authors.lastname: Ward
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yang
authors.forename: Huailan
authors.initials: H
authors.lastname: Guo
authors.forename: Ka
authors.initials: K
authors.lastname: He
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
mesh_terms: D000841:Anisomycin / Q000494:pharmacology; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D002460:Cell Line; D002788:Cholesterol Esters / Q000378:metabolism*; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008053:Lipid Mobilization; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000502:physiology; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
chemical_list: D002788:Cholesterol Esters; D020536:Enzyme Activators; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D000841:Anisomycin; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580