Abstract 18273: Novel Anti-Inflammatory Roles of Ikkε in Cardiac Macrophages Contributed to the Cardiac Recovery After Myocardial Infarction
Introduction: In the macrophages, NF-κB is a well-known master regulator of inflammation. IKK is an upstream kinase in NF-κB and the role of non-canonical IKKε is unknown in myocardial infarction (MI).
Methods and Results: RAW264.7 cells were stimulated with LPS with or without ChemA, an NF-κB inhibiting compound. MI was induced in rats and mice, and cardiac function by echocardiography. Mouse bone marrow was isolated and differentiated into macrophages (BMDM) by M-CSF. In stimulated RAW 264.7 cells, proinflammatory mediators such as iNOS, p65 NF-κB, canonical IKKα/β/γ, as well as noncanonical IKKε/TBK1 were notably inhibited by ChemA. Vehicle (Veh) or ChemA were given to MI rats for 2 weeks, and EF was 33.5±4.7 % in the Veh group and 43.5±2.0 % in the ChemA group (p<0.05). The infiltrated cardiac macrophages highly expressed IKKε in the ChemA group. ChemA inhibited IKKε in response to LPS stimulation in RAW264.7 cells, whereas the compound upregulated IKKε in cardiac macrophages along with functional recovery after MI. To clarify the role of IKKε, MI was induced in IKKε KO. Unexpectedly, EF was 42.2±3.4 % in the wild type group and 37.5±5.0 % in the KO group (p<0.05). NLRP3 inflammasome activation is a critical signaling event for the production of inflammatory cytokines. In LPS-stimulated RAW264.7 cells, ChemA blocked the inductions of NLRP3, IL-1β, and IL-18. Conversely, inductions of NLRP3, IL-1β, and IL-18 were higher in LPS-stimulated BMDM from KO mice than WT mice (p<0.05).
Conclusions: The therapeutic effect of ChemA was resulted from stronger inhibition of canonical NF-κB over noncanonical IKKε. Our findings showed IKKε limited chronic inflammation in cardiac macrophages. Here, we suggest that selective inhibition of canonical NF-κB and discriminated activation of IKKε might be an outstanding strategy for cardiac repair.
- Myocardial infarction
- Inflammation and inflammatory markers
- Immunologic factors
- Cardiovascular therapeutics
Author Disclosures: J. Kim: None. W. Kang: None. H. Jeong: None. M. Cho: None. Y. Kim: None. Y. Ahn: None.
- © 2016 by American Heart Association, Inc.