A necrotic core formed in an advanced atherosclerosis (AS) lesion is a collection of necrotic macrophages(M ) surrounded by inflammatory cells, which contributes to inflammation, plaque disruption, and thrombosis,and eventually develops into a vulnerable plaque. Ordinarily, rapid phagocytic clearance (efferocytosis) by M prevents necrotic core formation, but increasing evidence indicates that efferocytosis is defective in advancedlesions. Although efferocytosis can be up-regulated by HMG Co-A reductase inhibitors (statins)1-3, thecomprehensive regulatory mechanism for efferocytosis remains unclear. In the study, we show that statins/ACstreatment activates ERK5 kinase in M and accelerates efferocytosis via secretion of opsonins and M2 M polarization, whereas these responses are inhibited in M derived from M specific ERK5 knock-out (ERK5-MKO) mice. Indeed, ERK5-MKO/LDLR-/- mice showed increased necrotic core and AS formation. On the otherhand, p90RSK activated by angiotensin II (AngII) inhibited the ERK5 role in M functions by inhibiting ERK5transcriptional activity via ERK5 S496 phosphorylation. In addition, M -specific wild type-p90RSK transgenic(WT-p90RSK-MTg) crossing to LDLR-/- mice exhibited accelerated formation of necrotic core and AC formation.It suggests that the interplay between p90RSK and ERK5 are critical for the regulation of various M functions.We therefore hypothesize that statin/ACs-mediated ERK5 kinase activation is a key step in efferocytosis, whichinhibits AS and necrotic core formation, while p90RSK activation under AngII, or in advanced atheroscleroticlesions, inhibits efferocytosis via inhibiting ERK5. We will design experiments to address this hypothesis usingan in vivo and in vitro approach. The three specific aims of this proposal are 1) We will test the hypothesis thatthe balance between p90RSK and ERK5 activation under AngII, statins, or CSF-1 stimulation differentiallyregulates M functions such as proliferation, apoptosis, M1/M2 phenotypes, and efferocytosis, 2) We willinvestigate our hypothesis that p90RSK activation induced by AngII or in advanced plaques inhibits ERK5transcriptional activity and efferocytosis, which promotes the formation of AS plaques and necrotic cores, and3) We will test the hypothesis that ERK5 activation or inhibition of p90RSK increases efferocytosis and inhibitsAS and necrotic core formation via up-regulation of Mfge8. The significance of our study is in providing amechanistic understanding of the clinically well-described cardiac risk of acute athero-thrombotic vasculardisease in advanced atherosclerotic lesions. Also, understanding the role and molecular mechanisms of ERK5-mediated efferocytosis and inhibition of the necrotic core and AS formation should provide insight into thecause of acute atherothrombotic vascular diseases and possibly reveal novel therapeutic targets.

Public Health Relevance

The key role of efferocytosis in atherosclerosis and the stability of vulnerable plaques have become increasingly evident. We anticipate that specific macrophage ERK5 downregulation and subsequent reduced expression of ERK5 targeted molecules including efferocytosis-related genes make macrophages atheroprone and form a vulnerable plaque accumulating apoptotic debris and necrotic core. Mechanistically; we have found that p90RSK regulates the ERK5 effects on the efferocytosis process as a negative regulator. Therefore; the activation of ERK5 and inhibition of p90RSK activity could emerge as novel therapeutic targets to tackle the highly relevant problem of managing vulnerable plaques from rupture.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL118462-01A1
Application #
8628358
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Hasan, Ahmed AK
Project Start
2014-01-02
Project End
2018-12-31
Budget Start
2014-01-02
Budget End
2014-12-31
Support Year
Fiscal Year
2014
Total Cost
$345,375
Indirect Cost
$120,375
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627