Novel mechanisms of the thrombotic complications of atherosclerosis

动脉粥样硬化血栓并发症的新机制

• 批准号: 9977702
• 负责人: Peter Libby
• 金额: $ 42.1万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977702
• 关键词: Arginine deiminase; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Biological; Clinic; Clinical; Clinical Data; Collagen; Collection; Complication; Coronary artery; Data; Disease; Endothelium; Event; Glycosaminoglycans; Hematopoiesis; Human; Individual; Injury; Insulin Resistance; Intervention; Knowledge; Lesion; Link; Lipids; Low-Density Lipoproteins; Marshal; Medical; Metabolic syndrome; Molecular; Molecular Probes; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; Obesity; Pathologic; Patients; Preparation; Process; Proteins; Proteoglycan; Publishing; Research; Risk; Risk Factors; Role; Rupture; Site; Somatic Mutation; Testing; Thinness; Thrombosis; Ursidae Family; Variant; Work; Yawning; acute coronary syndrome; atherosclerosis risk; atherothrombosis; cardiovascular risk factor; demographics; experimental study; extracellular; granulocyte; improved; in vivo; in vivo evaluation; inhibitor/antagonist; interstitial; macrophage; neutrophil; novel; novel therapeutics; pre-clinical; profiles in patients; young woman

Current clinical and pathological data suggest an ongoing major shift in the mechanisms of the thrombotic complications of human atherosclerosis. Human plaques contain less lipid and fewer macrophages in the statin era. Patients with acute coronary syndromes (ACS) include more and younger women, and obese and insulin resistant individuals. ST segment elevation myocardial infarctions (STEMIs) have declined as non-STEMIs have risen. We have marshaled evidence for a shift in the mechanisms of ACS. In the current era of intense LDL lowering, rupture of so-called “vulnerable plaques” now causes fewer acute coronary syndromes while superficial erosion is increasing as a proportion of ACS. While we have considerable mastery of the biological basis of plaque rupture, and the mechanisms by which lipid- lowering can attenuate this trigger of thrombosis, a striking knowledge gap yawns regarding mechanisms of superficial erosion. This process differs substantially from plaque rupture: human lesions that have provoked erosion generally lack a prominent lipid collection, have few macrophages and more proteoglycan and glycosaminoglycans (GAGs) rather than thin, collagen-poor fibrous caps. Recent clinical data suggest that the management ACS due to erosion, unlike those due to plaque rupture, does not require urgent invasive treatment, rendering the quest for greater understanding of the mechanisms of erosion medically imperative. Our newly published data suggest a role for neutrophils (polymorphonuclear leukocytes, PMN), and neutrophil extracellular traps (NETs) in superficial erosion. We will use a validated experimental preparation in mice that superimposes disturbed flow on a GAG and proteoglycan-rich intima, conditions that pertain to human plaques complicated by superficial erosion, to probe molecular and cellular mechanisms of this type of thrombotic complication of atherosclerosis. My proposal centers on the unified theme of PMN and NET functions. 1) We will test using mice deficient in peptidyl arginine deiminase 4 (PAD4) the hypothesis that at sites of flow disturbance in arteries with erosion-like intimas, NETs participate critically in local endothelial injury and thrombosis. 2) We will test the hypothesis that myeloid-related protein (MRP) 8/14, we have previously implicated in arterial diseases, contributes to local NETosis and in endothelial injury and thrombosis at sites of flow disturbance in arteries with erosion-like intimas. 3) We test the hypothesis that mice bearing in myeloid cells the V617F Jak2 variant associated with clonal hematopoiesis and increased atherosclerotic risk in humans, will have aggravated NETosis and endothelial injury and thrombosis at sites of flow disturbance in arteries with erosion-like intimas. This aim will not only provide mechanistic information regarding superficial erosion, but will help elucidate the mechanism of increased thrombotic events in individuals who bear this somatic mutation common in those with clonal hematopoiesis, a newly recognized potent cardiovascular risk factor. Our studies will also explore novel therapeutic strategies immediately translatable to the clinic.

当前的临床和病理数据表明，该机制的重大转变 人动脉粥样硬化的血栓形成并发症。人斑块含有较少的脂质，较少 他汀类药物时代的巨噬细胞。急性冠状动脉综合征（AC）的患者包括更多以下 妇女，肥胖和胰岛素耐药的个体。 ST段海拔心肌梗塞（STEMIS） 随着非茎的增长，已经下降了。我们已提出证据表明ACS机制发生了变化。 在当前降低LDL的时代，所谓的“易受伤害斑块”的破裂现在会导致更少 急性冠状动脉综合征虽然表面侵蚀的增加是AC的一部分。当我们 对斑块破裂的生物学基础具有相当大的掌握，以及脂质的机制 降低可以减弱这种血栓形成的触发因素，这是关于机制的打击知识差距 表面侵蚀。这个过程与斑块破裂有很大不同：具有 挑衅的侵蚀通常缺乏突出的脂质系列，几乎没有巨噬细胞和更多的蛋白聚糖 和糖胺聚糖（插科打），而不是薄的胶原纤维纤维帽。最近的临床数据表明 由于侵蚀而导致的管理AC，与斑块破裂不同，不需要紧急侵入性 治疗，使人们寻求对侵蚀机制在医学上的命令率的更深入。 我们新发表的数据表明中性粒细胞（多形核白细胞，PMN）和中性粒细胞的作用 浅表侵蚀中的细胞外陷阱（网）。我们将在小鼠中使用经过验证的实验制剂 叠加在堵嘴和蛋白聚糖丰富的内膜上的叠加流动，与人斑有关 通过表面侵蚀复杂，以探测这种血栓形成的分子和细胞机制 动脉粥样硬化的并发症。我的建议集中在PMN和净功能的统一主题上。 1）我们 将使用缺乏肽基精氨酸脱氨酶4（PAD4）的小鼠进行测试。 网络扰动类似侵蚀的内膜的动脉，网络批判性地参与局部内皮损伤和 血栓形成。 2）我们将检验以下假设：髓样相关蛋白（MRP）8/14，我们以前有 在动脉疾病中实施，有助于局部Netosis，内皮损伤和血栓形成 具有类似侵蚀性内膜的动脉流动障碍。 3）我们检验了骨髓中的小鼠的假设 细胞与克隆造血相关的V617F JAK2变体，并增加了动脉粥样硬化风险 人类将在流动灾难部门的肠病和内皮损伤和血栓形成 具有侵蚀性内膜的动脉。这个目标不仅将提供有关肤浅的机械信息 侵蚀，但将有助于阐明携带这一问题的个体中血栓形成事件增加的机制 在患有克隆造血的人中常见的体细胞突变，这是一种新认识的潜在心血管风险 因素。我们的研究还将探索可立即转化为诊所的新型治疗策略。