Journal
FASEB JOURNAL
Volume 31, Issue 2, Pages 674-686Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201600669R
Keywords
cardiovascular research; IL-8; MIP-1 beta/CCL4; modified lipoproteins; scavenger receptor CD36
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Funding
- Robert Bosch Stiftung, Stuttgart, Germany
- IZEPHA Grant Tubingen-Stuttgart, Germany
- EU-Cinazept Grant
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The first ATP-competitive p38 alpha MAPK/MAPK14 inhibitor with excellent in vivo efficacy and selectivity, skepinone-L, is now available. We investigated the impact of selective p38 alpha MAPK/MAPK14 inhibition on enzymatically modified LDL (eLDL) stimulated human monocytes with its implications for atherosclerosis. Among the different p38 MAPK isoforms, p38 alpha/MAPK14 was the predominantly expressed and activated isoform in isolated human peripheral blood monocytes. Moreover, eLDL colocalized with macrophages positive for p38 alpha 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-1 beta/CCL4 (macrophage inflammatory protein-1 beta/chemokine, CC motif, ligand 4). Inhibition of a key signaling molecule of the p38 MAPK pathway, p38 alpha 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.
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