Abstract 15966: Macrophage P90rsk Accelerates Atherosclerosis by Inhibiting Efferocytosis
Backgrounds: We have previously reported that ERK5 activation promotes efferocytosis and downregulates atherosclerosis (AS). The impairment of efferocytosis in advanced plaque has been suggested, but the regulatory mechanisms are largely unknown.
Methods and Results: Immunohistochemistry studies on LDLR-/- mice showed that p90RSK activation was significantly up-regulated in advanced plaques, especially in MΦ. We have reported that p90RSK activation inhibits ERK5 transcriptional activity and intensifies endothelial inflammation via phosphorylation of ERK5 S496. In this study, we investigated the role of MΦ p90RSK in regulating ERK5 and efferocytosis. Angiotensin II (AngII) is known to impair efferocytosis and we found that 200 nM AngII activated p90RSK. AngII treatment and adenovirus (Ad)-wild type (WT) p90RSK overexpression inhibited ERK5 transcriptional activity and subsequent expression of the efferocytosis- and M2-type-related genes. These inhibitions were completely reversed by a highly selective p90RSK inhibitor, FMK-MEA. To determine the unique role of MΦ p90RSK in AS, we generated floxed WT- and dominant negative (DN, K94A/K447A)-p90RSK mice and crossed them with LysMCre/LDLR-/- mice (WT (or DN)-p90RSK-MTg /LDLR-/-). A significant increase in ERK5 S496 phosphorylation and down-regulation of efferocytosis-related gene expression were observed in the peritoneal MΦ from WT-p90RSK-MTg mice. We also injected fluorescently labeled apoptotic cells (AC) in the peritoneum of the mice to study AC clearance in vivo. Delayed clearance by resident peritoneal MΦ was observed in WT- but not in DN-p90RSK-MTg, suggesting a key role of p90RSK activation in regulating efferocytosis. To evaluate the role of MΦ p90RSK on AS, WT or DN-p90RSKMTg/LDLR-/- mice were fed a high cholesterol diet for 16-week. We found that AS and necrotic core formations were significantly accelerated in WT- but not DN-p90RSK-MTg/LDLR-/- animals. Taken together, these data suggest that MΦ p90RSK activation promotes AS via inhibiting ERK5-mediated efferocytosis and M2-type gene induction.
Conclusion: The lack of balance between p90RSK and ERK5 activities in advanced plaques is a key event for determining efferocytosis and subsequent vulnerable plaque development.
Author Disclosures: K. Heo: None. M. Akaike: None. J. Taunton: Other; Significant; J.T. is a cofounder of Principia Biopharma, which has licensed FMK-MEA. K. Fujiwara: None. J. Abe: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.