title: Inhibition of p38 Mitogen-Activated Protein Kinase Enhances the Apoptosis Induced by Oxidized Low-Density Lipoprotein in Endothelial Progenitor Cells.
abstract: Oxidized low-density lipoprotein (oxLDL) is an important risk factor in the development of atherosclerosis. oxLDL has been shown to decrease endothelial progenitor cell (EPC) number by inducing apoptosis. p38 mitogen-activated protein kinase (MAPK) was shown to be activated by oxLDL and participated in the regulation of EPC number and function. However, the role of p38 remains unknown. Here, we show that oxLDL-induced p38 phosphorylation in EPCs is time and dose dependent. Treatment with antioxidant N-acetyl cysteine restored oxLDL-induced p38 phosphorylation to basal levels. LOX-1-blocking antibody also significantly decreased oxLDL-induced p38 phosphorylation. Interestingly, TUNEL staining showed that pretreatment with the p38 inhibitor SB203580 further increased oxLDL-induced apoptosis in EPCs. In accordance with these findings, pretreatment with SB203580 further attenuated Akt phosphorylation in EPCs challenged with oxLDL, indicating an interaction between Akt and p38 MAPK pathways. In agreement, inhibition of p38 MAPK further attenuated Akt phosphorylation and increased apoptosis in EPCs isolated from hypercholesterolemic ApoE-/- mice. In conclusion, p38 MAPK serves as an anti-apoptotic pathway by supporting Akt activity when EPCs are challenged with oxLDL.
authors.affiliation: Division of Vascular Surgery, University of Massachusetts Medical School, Worcester, Mass., USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Tie
authors.forename: Jinglian
authors.initials: J
authors.lastname: Yan
authors.forename: Julia A
authors.initials: JA
authors.lastname: Messina
authors.forename: Robert L
authors.initials: RL
authors.lastname: Raffai
authors.forename: Louis M
authors.initials: LM
authors.lastname: Messina
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D006937:Hypercholesterolemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; C495138:Olr1 protein, mouse; D047428:Protein Kinase Inhibitors; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases