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.

Enzyme-modified non-oxidized LDL (ELDL) induces human coronary artery smooth muscle cell transformation to a migratory and osteoblast-like phenotype

“…We showed that MAPKp38, ERK and NFkB activation were the top three canonical pathways in an unbiased Ingenuity pathway enriched network analysis of ELDL-treated HCASMC, and these findings were confirmed by ELISA. This is in agreement with a recent study demonstrating co-localization of immunohistochemical staining for ELDL and p38MAK/MAPK14 in human carotid endarterectomy tissue from atherosclerosis with high grade stenosis 44 . Among the wide-ranging downstream activities of phosphorylated p38MAPK, cytokine production is a component related to atherosclerosis and osteoblast differentiation 45 .…”

Exploring the Mechanism of Flavonoids Through Systematic Bioinformatics Analysis

“…For example, MAPK 14 in module 3 was found to participate in multiple cellular processes including cell proliferation, differentiation, transcriptional regulation and development ( Young, 2013 ). Also, it can be noted that MAPK 14 may related with atherosclerosis ( Cheng et al, 2017 ). Further, BCL2 in module 2 was a therapeutic target for chronic lymphocytic leukemia since it can regulate lymphocyte in blood by hindering cell apoptosis ( Ruefli-Brasse and Reed, 2017 ; Tahir et al, 2017 ) and PGD in module 5 was related with human cervical carcinoma ( Lee et al, 2014 ).…”

Nanoparticles for the Induction of Antigen-Specific Immunological Tolerance

“…Macrophages express various PS-specific scavenger receptors, such as Tyro3, Axl, and Mertk (collectively referred to as TAM receptors), TIM-3 and SCARF-1 that trigger the phagocytosis of dying cells and promote induction of a tolerogenic phenotype, such as the increase in IL-10 and TGFβ secretion, and a decrease in NF-κB signaling and TNFα, IL-1β, and IL-12 secretion ( 97 ). Encapsulating coagulation FVIII in PS-bearing liposomes was effective to prevent the formation of inhibitory anti-FVIII antibodies in hemophilia A animals even when animals were challenged with FVIII alone ( 53 , 57 , 98 , 99 ). A similar approach was demonstrated with alpha-glucosidase (GAA) in a mouse model of Pompe disease.…”