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Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL‐stimulated human monocytes: implications for atherosclerosis
Author(s) -
Cheng Fei,
Twardowski Laura,
Fehr Sarah,
Aner Christoph,
Schaeffeler Elke,
Joos Thomas,
Knorpp Thomas,
Dorweiler Bernhard,
Laufer Stefan,
Schwab Matthias,
Torzewski Michael
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201600669r
Subject(s) - p38 mitogen activated protein kinases , mapk14 , mapk/erk pathway , microbiology and biotechnology , chemokine , foam cell , kinase , monocyte , mitogen activated protein kinase , biology , chemistry , macrophage , map kinase kinase kinase , biochemistry , receptor , immunology , in vitro
The first ATP‐competitive p38a MAPK/MAPK14 inhibitor with excellent in vivo efficacy and selectivity, skepinone‐L, is now available. We investigated the impact of selective p38a MAPK/MAPK14 inhibition on enzymatically modified LDL (eLDL) stimulated human monocytes with its implications for atherosclerosis. Among the different p38 MAPK isoforms, p38a/MAPK14 was the predominantly expressed and activated isoform in isolated human peripheral blood monocytes. Moreover, eLDL colocalized with macrophages positive for p38a 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 eLDLtriggered apoptosis, and inhibited eLDL‐stimulated secretion of IL‐8 and MIP‐1b/CCL4 (macrophage inflammatory protein‐1b/chemokine, CC motif, ligand 4). Inhibition of a key signaling molecule of the p38 MAPK pathway, p38a 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 p38a MAP kinase/MAPK14 inhibition in enzymatically modified LDL‐stimulated human monocytes: implications for atherosclerosis. FASEB J. 31, 674–686 (2017). www.fasebj.org