p90RSK-ERK5 module, efferocytosis, and vulnerable plaque formation

p90RSK-ERK5 模块、胞吞作用和易损斑块形成

• 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
• 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

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（由适用提供）：在晚期动脉粥样硬化（AS）病变中形成的坏死核是由炎症细胞周围的坏死巨噬细胞（M€）集合，这有助于炎症，斑块破坏和血栓形成，并最终发展为脆弱的斑块。通常，巨噬细胞的快速吞噬清除率（ex孢子菌病）可防止坏死核的形成，但越来越多的证据表明伴有胞吞作用在晚期病变中有缺陷。尽管HMG Co-A可以上调肿瘤病，但降低了抑制剂（他汀类药物）1-3，但肿瘤性胞吐作用的综合调节机制尚不清楚。在这项研究中，我们表明他汀类药物/ACS治疗激活了M的ERK5激酶，并通过分泌Opsonins和M2 M earlization加速了传染性细胞增多，而这些反应抑制了源自巨噬细胞特异性ERK5敲除（ERK5- MKO）小鼠的M。实际上，ERK5-MKO/LDLR - / - 小鼠显示出坏死核的增加和形成。另一方面，血管紧张素II（ANGII）激活的P90RSK通过通过ERK5 S496磷酸化抑制ERK5转录活性来抑制ERK5在M函数中的作用。此外，M€特异性野生型P90RSK转基因（WT-P90RSK-MTG）交叉至LDLR - / - 小鼠暴露了坏死核和AC形成的加速形成。这表明P90RSK和ERK5之间的相互作用对于调节各种M函数至关重要。因此，我们假设他汀类药物/ACS介导的ERK5激酶激活是炎症细胞增多症的关键步骤，它抑制AS和坏死性核心形成，而p90RSK在ANGII下或晚期动脉粥样硬化病变中的p90RSK激活，通过抑制ERK5抑制ex炎。我们将设计实验，以使用体内和体外方法来解决这一假设。 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 simulation 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斑块抑制ERK5的转录活性和肿瘤病，从而促进了AS斑块和坏死核的形成，3）我们将检验以下假说，即ERK5激活或抑制P90RSK会增加递增和抑制作为通过UP-GENECERATION MFEN-MFGE8。我们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血管疾病的临床良好描述的心脏风险的机械理解。同样，了解ERK5介导的胞吞作用和抑制坏死核的作用和分子机制，并作为形成应洞悉急性动脉粥样硬化性血栓性血管性血管疾病的原因，并可能揭示出新的治疗靶标。