p90RSK-ERK5 module, efferocytosis, and vulnerable plaque formation

p90RSK-ERK5 模块、胞吞作用和易损斑块形成

基本信息

批准号：
8788951
负责人：
Jun-Ichi Abe
金额：
$ 39.4万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788951
关键词：
Abbreviations Acute Address Adenovirus Vector Angiotensin II Apoptosis Apoptotic Arterial Fatty Streak Atherosclerosis Biology Blood Vessels Bone Marrow Cardiac Cells Collection Data Dominant-Negative Mutation Down-Regulation EGF gene Equilibrium Event Exhibits Gene Expression Genes Health In Vitro Inflammation Inflammatory Knock-out Knockout Mice Lesion Link Liquid substance MAPK7 gene Macrophage Colony-Stimulating Factor Mediating Molecular Mus Myeloid Cells Necrosis Opsonin Oxidoreductase Peritoneum Phagocytosis Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Process RPS6KA gene Regulation Risk Role Rupture Scheme Sclerosis Testing Thrombosis Time Transactivation Transgenic Mice Transgenic Organisms Up-Regulation Vascular Diseases Work acute coronary syndrome base cell type design in vivo inhibitor/antagonist insight macrophage milk fat globule mutant new therapeutic target novel prevent research study response

项目摘要

DESCRIPTION (provided by applicant): 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 macrophages prevents necrotic core formation, but increasing evidence indicates that efferocytosis is defective in advanced lesions. Although efferocytosis can be up-regulated by HMG Co-A reductase inhibitors (statins)1-3, the comprehensive regulatory mechanism for efferocytosis remains unclear. In the study, we show that statins/ACs treatment 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 macrophage specific ERK5 knock-out (ERK5- MKO) mice. Indeed, ERK5-MKO/LDLR-/- mice showed increased necrotic core and AS formation. On the other hand, p90RSK activated by angiotensin II (AngII) inhibited the ERK5 role in M¿ functions by inhibiting ERK5 transcriptional 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, which inhibits AS and necrotic core formation, while p90RSK activation under AngII, or in advanced atherosclerotic lesions, inhibits efferocytosis via inhibiting ERK5. We will design experiments to address this hypothesis using an in vivo and in vitro approach. The three specific aims of this proposal are 1) We will test the hypothesis that the balance between p90RSK and ERK5 activation under AngII, statins, or CSF-1 stimulation differentially regulates M¿ functions such as proliferation, apoptosis, M1/M2 phenotypes, and efferocytosis, 2) We will investigate our hypothesis that p90RSK activation induced by AngII or in advanced plaques inhibits ERK5 transcriptional activity and efferocytosis, which promotes the formation of AS plaques and necrotic cores, and 3) We will test the hypothesis that ERK5 activation or inhibition of p90RSK increases efferocytosis and inhibits AS and necrotic core formation via up-regulation of Mfge8. The significance of our study is in providing a mechanistic understanding of the clinically well-described cardiac risk of acute athero-thrombotic vascular disease 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 the cause of acute atherothrombotic vascular diseases and possibly reveal novel therapeutic targets.

描述（由申请人提供）：晚期动脉粥样硬化（AS）病变中形成的坏死核心是被炎症细胞包围的坏死巨噬细胞（M¿）的集合，这会导致炎症、斑块破坏和血栓形成，并最终发展成通常，巨噬细胞的快速吞噬清除（胞吞作用）可防止坏死核心形成，但越来越多的证据表明，胞吞作用。尽管HMG Co-A还原酶抑制剂（他汀类药物）1-3可以上调胞吞作用，但胞吞作用的综合调节机制仍不清楚。在这项研究中，我们表明他汀类药物/ACs治疗会激活ERK5激酶。在 M¿并通过分泌调理素和 M2 M¿ 加速胞吞作用极化，而这些反应在 M¿事实上，ERK5-MKO/LDLR-/- 小鼠表现出坏死核心和 AS 形成增加，另一方面，血管紧张素 II (AngII) 激活的 p90RSK 抑制了 ERK5。 M 中的角色通过 ERK5 S496 磷酸化抑制 ERK5 转录活性来发挥作用。 -特异性野生型 p90RSK 转基因 (WT-p90RSK-MTg) 与 LDLR-/- 小鼠杂交显示坏死核心和 AC 形成加速，这表明 p90RSK 和 ERK5 之间的相互作用对于各种 M¿因此，我们认为他汀类药物/ACs 介导的 ERK5 激酶激活是胞吞作用的关键步骤，它抑制 AS 和坏死核心形成，而 AngII 下或晚期动脉粥样硬化病变中的 p90RSK 激活通过抑制 ERK5 来抑制胞吞作用。使用体内和体外方法来解决这一假设的实验该提案的三个具体目标是 1) 我们将测试平衡的假设。 AngII、他汀类药物或 CSF-1 刺激下 p90RSK 和 ERK5 激活之间存在差异调节 M¿ 2) 我们将研究我们的假设，即 AngII 或晚期斑块中诱导的 p90RSK 激活会抑制 ERK5 转录活性和胞吞作用，从而促进 AS 斑块和坏死核心的形成， 3) 我们将检验以下假设：ERK5 激活或 p90RSK 抑制会增加胞吞作用并抑制 AS 和通过上调 Mfge8 来形成坏死核心，我们的研究的意义在于提供对晚期动脉粥样硬化病变中急性动脉粥样硬化性血管疾病的临床详细描述的心脏风险的机制理解。 ERK5 介导的胞吞作用以及对坏死核心和 AS 形成的抑制应该有助于深入了解急性动脉粥样硬化性血管疾病的原因，并可能揭示新的治疗靶点。