Novel mechanisms of the thrombotic complications of atherosclerosis

目前的临床和病理数据表明，糖尿病的发病机制正在发生重大转变。 人类动脉粥样硬化的血栓并发症。人类斑块含有更少的脂肪和更少的 他汀类药物时代的巨噬细胞。急性冠状动脉综合征(ACS)患者包括更多和更年轻的患者 女性，以及肥胖和胰岛素抵抗的人。ST段抬高心肌梗死(STEMI) 随着非STEMI的上升而下降。我们已经收集了急性冠脉综合征机制转变的证据。 在当前低密度脂蛋白大幅降低的时代，所谓的“易损斑块”的破裂现在引起的 急性冠脉综合征和体表糜烂在急性冠脉综合征中所占的比例正在增加。当我们 对斑块破裂的生物学基础有相当的掌握，以及脂类-血管紧张素转换酶 降低血压可以减弱血栓形成的触发因素，这是一个关于血栓形成机制的惊人的知识鸿沟 表面侵蚀。这一过程与斑块破裂有很大不同：人类病变具有 引起的糜烂一般缺乏明显的脂质聚集，有少量的巨噬细胞和较多的蛋白多糖 和糖胺多聚糖(GAG)，而不是薄的，缺乏胶原的纤维帽。最近的临床数据表明 与斑块破裂不同的是，由于侵蚀导致的急性冠脉综合征不需要紧急侵入性治疗。 因此，医学上迫切需要更深入地了解侵蚀的机制。 我们最新发表的数据表明，中性粒细胞(中性粒细胞，PMN)和中性粒细胞 浅层侵蚀中的细胞外陷阱(Net)。我们将在小鼠身上使用一种经过验证的实验制剂 将干扰流叠加在插嘴和富含蛋白多糖的内膜上，这是与人类斑块有关的条件 并发浅表糜烂，探讨该类型血栓形成的分子和细胞机制 动脉粥样硬化的并发症。我的建议是围绕PMN和Net职能的统一主题。1)我们 将使用肽精氨酸脱亚胺酶4(PAD4)缺陷的小鼠来测试这一假说 具有侵蚀样内膜的动脉紊乱，Net在局部血管内皮损伤和 血栓形成。2)我们将检验髓系相关蛋白(MRP)8/14的假设，我们之前已经 与动脉疾病有关，导致局部网织红细胞增多症以及血管内皮损伤和血栓形成 动脉内有侵蚀样内膜的血流紊乱。3)我们检验了这样的假设，即小鼠在髓系中生育 细胞V617F JAK2变异与克隆性造血和动脉粥样硬化风险增加相关 人类，在血流紊乱的部位会加重网织红细胞增多症和内皮损伤和血栓形成 有侵蚀样内膜的动脉。这一目标不仅将提供关于表面上的机械信息 侵蚀，但将有助于阐明携带这种疾病的个体血栓事件增加的机制 克隆造血者中常见的体细胞突变，这是一种新发现的潜在心血管风险 因素。我们的研究还将探索可立即移植到临床的新的治疗策略。

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.