Abstract 390: Macrophage p90RSK Activation Inhibits Efferocytosis via Phosphorylation of ERK5 S496 and Intensifies Atherosclerosis Plaque Formation
Backgrounds: We previously reported that ERK5 activation promoted efferocytosis and M2 macrophage (MΦ) polarization in advanced plaque formation. Although we recently found the critical role of p90RSK activation and its inhibitory effect on the ERK5 transcriptional activity via S496 phosphorylation, it’s still unclear how MΦ p90RSK interplay with ERK5 in the atherosclerosis (AS) development.
Methods and Results: We found that p90RSK activation was significantly increased in advanced atherosclerotic lesion. It has been reported that angiotensin II (AngII) type I receptor (AT1) of MΦ accelerates AS by impairing efferocytosis and we found 200 nM AngII activated p90RSK, but not ERK5. Interestingly, p90RSK inhibitor, FMK-MEA treatment significantly increased efferocytosis-related opsonins and M2-type genes mRNA levels, whereas AngII failed to inhibit these increases, suggesting a crucial role of p90RSK activation in regulating efferocytosis and inflammation. A significantly enhanced level of ERK5-S496 phosphorylation was observed in the peritoneal MΦ from macrophage-specific wild type-p90RSK transgenic (WT-p90RSK-MTg) mice. WT-p90RSK-MTg/LDLR-/- mice fed HCD accelerated AS and necrotic core formations compared with NLC/LDLR-/- mice, suggesting the pro-atherogenic effect of MΦ p90RSK. To determine the roles of p90RSK and ERK5 activation and its interplay in regulating MΦ proliferation, we studied effects of colony stimulating factor 1 (CSF-1), statins, and AngII on MΦ proliferation. First, we examined p90RSK activation and ERK5 transcriptional activity and found AngII and CSF-1, but not pitavastatin, activated p90RSK, while ERK5 transcriptional activity was increased by CSF-1 and pitavastatin, but not by AngII. However, only CSF-1, but not AngII and pitavastatin, promoted MΦ proliferation. Interestingly, CSF-1 lost its proliferative effect in MΦ isolated from ERK5-MKO or in those treated with FMK-MEA, suggesting that activation of both p90RSK and ERK5 are necessary, and only one of them is not sufficient, to promote MΦ proliferation.
Conclusion: These data strongly support that the balance between p90RSK and ERK5 would be a key factor for the regulation of MΦ propagation and functions, and regulates AS formation.
Author Disclosures: K. Heo: None. M. Akike: None. J. Taunton: None. 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.