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.
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.
| Le, Nhat-Tu; Abe, Jun-Ichi (2018) MicroRNA 199a and the eNOS (Endothelial NO Synthase)/NO Pathway. Arterioscler Thromb Vasc Biol 38:2278-2280 |
| Ko, Kyung Ae; Wang, Yin; Kotla, Sivareddy et al. (2018) Developing a Reliable Mouse Model for Cancer Therapy-Induced Cardiovascular Toxicity in Cancer Patients and Survivors. Front Cardiovasc Med 5:26 |
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| Le, Nhat-Tu; Sandhu, Uday G; Quintana-Quezada, Raymundo A et al. (2017) Flow signaling and atherosclerosis. Cell Mol Life Sci 74:1835-1858 |
| Abe, Jun-Ichi; Sandhu, Uday G; Hoang, Nguyet Minh et al. (2017) Coordination of Cellular Localization-Dependent Effects of Sumoylation in Regulating Cardiovascular and Neurological Diseases. Adv Exp Med Biol 963:337-358 |
| Le, Nhat-Tu; Martin, James F; Fujiwara, Keigi et al. (2017) Sub-cellular localization specific SUMOylation in the heart. Biochim Biophys Acta Mol Basis Dis 1863:2041-2055 |
| Mao, Yun; Luo, Wei; Zhang, Lin et al. (2017) STING-IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity. Arterioscler Thromb Vasc Biol 37:920-929 |
| Abe, Jun-Ichi; Martin, James F; Yeh, Edward T H (2016) The Future of Onco-Cardiology: We Are Not Just ""Side Effect Hunters"". Circ Res 119:896-9 |
| Heo, Kyung-Sun; Berk, Bradford C; Abe, Jun-Ichi (2016) Disturbed Flow-Induced Endothelial Proatherogenic Signaling Via Regulating Post-Translational Modifications and Epigenetic Events. Antioxid Redox Signal 25:435-50 |
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