title: Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis.
abstract: The first ATP-competitive p38α MAPK/MAPK14 inhibitor with excellent in vivo efficacy and selectivity, skepinone-L, is now available. We investigated the impact of selective p38α MAPK/MAPK14 inhibition on enzymatically modified LDL (eLDL) stimulated human monocytes with its implications for atherosclerosis. Among the different p38 MAPK isoforms, p38α/MAPK14 was the predominantly expressed and activated isoform in isolated human peripheral blood monocytes. Moreover, eLDL colocalized with macrophages positive for p38α MAPK/MAPK14 in human carotid endarterectomy specimens. Using the human leukemia cell line THP-1 and/or primary monocyte-derived macrophages, skepinone-L inhibited eLDL-induced activation of the p38 MAPK pathway, inhibited eLDL induced expression of both cluster of differentiation 36 (CD36) and ATP-binding cassette, subfamily A, member 1 (ABCA1), without a net effect on foam cell formation, had a cell- and time-dependent effect on eLDL-triggered apoptosis, and inhibited eLDL-stimulated secretion of IL-8 and MIP-1β/CCL4 (macrophage inflammatory protein-1β/chemokine, CC motif, ligand 4). Inhibition of a key signaling molecule of the p38 MAPK pathway, p38α MAPK/MAPK14, by selective inhibitors like skepinone-L, conclusively facilitates elucidation of the impact of the complex network of p38 MAPK signaling on atherogenesis and might provide a promising therapeutic tool to prevent inflammatory cascades in atherosclerosis.-Cheng, F., Twardowski, L., Fehr, S., Aner, C., Schaeffeler, E., Joos, T., Knorpp, T., Dorweiler, B., Laufer, S., Schwab, M., Torzewski, M. Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis.
authors.affiliation: Department of Laboratory Medicine, Robert-Bosch-Hospital, Stuttgart, Germany.|Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
authors.forename: Fei
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Department of Laboratory Medicine, Robert-Bosch-Hospital, Stuttgart, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Twardowski
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fehr
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Aner
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.affiliation: Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Joos
authors.affiliation: Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Knorpp
authors.affiliation: Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dorweiler
authors.affiliation: Institute of Pharmacy, University of Tübingen, Tübingen, Germany; and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.|Institute of Pharmacy, University of Tübingen, Tübingen, Germany; and.|Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Department of Laboratory Medicine, Robert-Bosch-Hospital, Stuttgart, Germany; michael.torzewski@rbk.de.|Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Torzewski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D008078:Cholesterol, LDL / Q000494:pharmacology*; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D008078:Cholesterol, LDL; D003986:Dibenzocycloheptenes; C572387:skepinone-L; D048308:Mitogen-Activated Protein Kinase 14; D053148:Caspase 3; D053179:Caspase 7
keywords: IL-8; MIP-1β/CCL4; cardiovascular research; modified lipoproteins; scavenger receptor CD36