HDL, platelet progenitors, atherosclerosis and thrombosis

HDL、血小板祖细胞、动脉粥样硬化和血栓形成

• 批准号: 8694996
• 负责人: NAN WANG
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694996
• 关键词: ATP-Binding Cassette Transporters; Animals; Antiatherogenic; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Models; Blood Platelets; Bone Marrow; Bone Marrow Transplantation; CBL gene; Cell membrane; Cell surface; Cells; Chemicals; Cholesterol; Cholesterol Homeostasis; Clinical; Coronary heart disease; Diet; Disease; Drug usage; Employee Strikes; Event; Fatty acid glycerol esters; Feedback; Figs - dietary; Foam Cells; General Population; Goals; Hemorrhagic Thrombocythemia; Hemostatic function; High Density Lipoproteins; Human; Infusion procedures; JAK2 gene; LYN gene; Link; Mediating; Megakaryocytes; Membrane; Membrane Microdomains; Modeling; Mus; Mutation; Myelofibrosis; Myeloproliferative disease; Patients; Phosphatidylserines; Phosphotransferases; Play; Preventive Intervention; Primary Myelofibrosis; Production; Regulation; Residual state; Risk; Risk Factors; Role; Rupture; Series; Signal Transduction; Stem cells; Surface; Testing; Therapeutic; Therapeutic Intervention; Thrombin; Thrombopoiesis; Thrombopoietin; Thrombosis; Thrombus; Ubiquitination; atherogenesis; atherothrombosis; cardiovascular disorder risk; cardiovascular risk factor; feeding; genetic variant; human MPL protein; inhibitor/antagonist; insight; macrophage; monocyte; neutrophil; novel; progenitor; public health relevance; research study; response; selective expression; sensor; thrombocytosis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Platelets play pivotal roles in hemostasis and platelet-related disorders. Activated platelets facilitate recruitment of monocytes and neutrophils to arterial wall and promote atherogenesis. Platelets also initiate the formation of thrombi on ruptured or eroded atherosclerotic plaques, causing clinical complications of atherosclerosis. A striking example occurs in myeloproliferative neoplasms (MPNs) such as essential thrombocytosis and primary myelofibrosis, in which increased platelet production is associated with prominent arterial thrombosis or athero-thrombosis. Aberrant platelet production has also been linked more broadly to cardiovascular risk in the general population. Substantial residual risks of cardiovascular disease in the general population and in patients with MPNs still remain, even with the access of current preventive and therapeutic interventions. HDL may be protective against coronary heart disease. A major hypothesis for the protective role of HDL is that it promotes cholesterol efflux from lesional atheroma cells. Recent studies indicate a key role of ATP-binding cassette transporters, ABCA1 and ABCG1 in promoting cholesterol efflux from macrophage foam cells to HDL. ABCG4 also promotes cholesterol efflux to HDL but ABCG4 is not expressed in macrophages. We found Abcg4 to be selectively expressed in bone marrow megakaryocyte progenitor cells (MkPs). Abcg4-/- MkPs showed defective cholesterol efflux to HDL and increased plasma membrane cholesterol. Abcg4-/- BM transplantation into hypercholesterolemic Ldlr-/- mice resulted in thrombocytosis, accelerated atherosclerosis and arterial thrombosis. Increased platelets reflected an expanded pool of MkPs and megakaryocytes, resulting from increased expression of the thrombopoietin (TPO) receptor (MPL) on the cell surface of MkPs. This reflected blunting of the negative feedback regulation of MPL by the E3 ubiquitin ligase, c-CBL. Further studies suggested that membrane-anchored Lyn kinase is inhibited by association with cholesterol-rich membrane microdomains in Abcg4-/- cells, resulting in impaired activation of c-CBL. We propose that HDL promotes cholesterol efflux from MkPs via ABCG4, activates Lyn and c-CBL, promotes ubiquitination and degradation of MPL and limits MPL-mediated proliferation signaling in response to TPO. HDL inhibits platelet production and suppresses thrombocytosis. We have proposed a series of studies to further test this hypothesis and assess infusion of HDL or pharmacological activation of LYN as potential treatment of atherosclerosis or atherothrombosis caused by aberrantly increased platelet production. Pharmacological activation of Lyn kinase and rHDL infusion will be assessed as potential therapy for MPNs induced by activating mutations of MPL and JAK2. We expect that the proposed studies will provide novel insights and therapeutic strategies for atherosclerosis and atherothrombosis associated with aberrantly increased platelet production.

描述（由申请人提供）：血小板在止血和血小板相关疾病中发挥关键作用。活化的血小板促进单核细胞和中性粒细胞募集到动脉壁并促进动脉粥样硬化形成。血小板还会在破裂或侵蚀的动脉粥样硬化斑块上引发血栓形成，导致动脉粥样硬化的临床并发症。一个引人注目的例子发生在骨髓增生性肿瘤（MPN）中，例如原发性血小板增多症和原发性骨髓纤维化，其中血小板生成增加与显着的动脉血栓形成或动脉粥样硬化血栓形成相关。异常的血小板生成也与普通人群的心血管风险有着更广泛的联系。即使采取了当前的预防和治疗干预措施，普通人群和 MPN 患者仍存在心血管疾病的大量残余风险。 HDL 可能具有预防冠心病的作用。 HDL 保护作用的一个主要假设是它促进胆固醇从病变动脉粥样硬化细胞中流出。最近的研究表明 ATP 结合盒转运蛋白 ABCA1 和 ABCG1 在促进胆固醇从巨噬细胞泡沫细胞流出至 HDL 方面发挥着关键作用。 ABCG4 还促进胆固醇流出至 HDL，但 ABCG4 在巨噬细胞中不表达。我们发现 Abcg4 在骨髓巨核细胞祖细胞 (MkPs) 中选择性表达。 Abcg4-/- MkPs 显示胆固醇向 HDL 的流出有缺陷，质膜胆固醇增加。 Abcg4-/- BM 移植到高胆固醇血症 Ldlr-/- 小鼠中会导致血小板增多、加速动脉粥样硬化和动脉血栓形成。血小板增加反映了 MkP 和巨核细胞池的扩大，这是由于 MkP 细胞表面血小板生成素 (TPO) 受体 (MPL) 表达增加所致。这反映了 E3 泛素连接酶 c-CBL 对 MPL 负反馈调节的减弱。进一步的研究表明，膜锚定的 Lyn 激酶通过与 Abcg4-/- 细胞中富含胆固醇的膜微结构域结合而受到抑制，从而导致 c-CBL 的激活受损。我们认为 HDL 通过 ABCG4 促进胆固醇从 MkP 流出，激活 Lyn 和 c-CBL，促进 MPL 泛素化和降解，并限制 MPL 介导的响应 TPO 的增殖信号传导。 HDL 抑制血小板生成并抑制血小板增多。我们提出了一系列研究来进一步检验这一假设，并评估 HDL 输注或 LYN 药理激活作为治疗由血小板生成异常增加引起的动脉粥样硬化或动脉粥样硬化血栓形成的潜在治疗方法。 Lyn 激酶和 rHDL 输注的药理学激活将被评估为通过激活 MPL 和 JAK2 突变诱导的 MPN 的潜在疗法。我们期望所提出的研究将为与血小板生成异常增加相关的动脉粥样硬化和动脉粥样硬化血栓形成提供新的见解和治疗策略。