IMM-H007, a novel small molecule inhibitor for atherosclerosis, represses endothelium inflammation by regulating the activity of NF-κB and JNK/AP1 signaling

• Published in: Toxicology and applied pharmacology Vol. 381; p. 114732
• Main Authors: Yu, Jinjin, Ming, Hong, Li, Henry You, Yu, Bin, Chu, Maoping, Zhu, Haibo, Zhu, Xinxing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2019
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Anti-Inflammatory Agents - pharmacology; Atherosclerosis; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Cyclin D1 - genetics; Cyclin D1 - metabolism; Endothelium Inflammation; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; H007; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Interleukin-1beta - genetics; Interleukin-6 - genetics; Interleukin-6 - metabolism; JNK/c-Jun Signaling; MAP Kinase Kinase 4 - metabolism; NF-kappa B - metabolism; NF-κB Signaling; Signal Transduction - drug effects; THP-1 Cells; Transcription Factor AP-1 - metabolism; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism; Endothelium Inflammation; NF-κB Signaling; H007; JNK/c-Jun Signaling
• DOI: 10.1016/j.taap.2019.114732
• ISSN: 0041-008X; 1096-0333

Endothelium inflammation has become a major risk factor for pathological development of atherosclerosis. IMM-H007 (H007), a small molecule compound, is previously reported to reduce inflammatory atherosclerosis. However, the regulatory role of H007 in endothelium inflammation is still unclear. Here, we characterize H007 as a critical repressor in regulation of endothelium inflammation. We find that H007 significantly inhibits monocyte adhesion to endothelial cells and its transendothelial migration. Mechanistically, H007 markedly represses TNFα-induced IκBα degradation and NF-κB nuclear translocation, therefore leading to NF-κB-mediated inflammatory suppression. Moreover, another inflammatory signaling JNK/c-Jun, which is always co-activated with NF-κB in response to pro-inflammatory stimuli, is also found to be restrained by H007 through reducing its phosphorylation status. Thus, we conclude that H007 negatively regulates endothelium inflammation through inactivating NF-κB and JNK/AP1 signaling. More importantly, this study provides us a new insight into understanding the molecular basis by which H007 regulates inflammatory atherosclerosis. [Display omitted] •H007 negatively regulates endothelium inflammation.•H007 regulates NF-κB signaling by repressing proteasome-mediated IκBα degradation.•H007 regulates JNK/c-Jun signaling through restraining its phosphorylation status.