Novel mechanisms of the thrombotic complications of atherosclerosis

目前的临床和病理数据表明，其机制正在发生重大转变。 人类动脉粥样硬化的血栓并发症。人体斑块含有较少的脂质和较少的 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、更年轻的患者 女性、肥胖者和胰岛素抵抗者。 ST 段抬高型心肌梗死 (STEMI) 随着非 STEMI 的增加而下降。我们收集了 ACS 机制发生转变的证据。 在当今大力降低低密度脂蛋白的时代，所谓的“易损斑块”的破裂现在导致更少的 急性冠状动脉综合征，而浅表糜烂在 ACS 中所占的比例正在增加。当我们 对斑块破裂的生物学基础以及脂质- 降低可以减弱这种血栓形成的触发因素，但有关机制方面存在显着的知识差距 表面侵蚀。这个过程与斑块破裂有很大不同：人类病变 引起的糜烂通常缺乏明显的脂质聚集，巨噬细胞很少，蛋白聚糖较多 和糖胺聚糖（GAG），而不是薄的、缺乏胶原蛋白的纤维帽。最近的临床数据表明 与斑块破裂引起的ACS不同，由于侵蚀引起的ACS不需要紧急侵入性治疗 治疗，使得在医学上迫切需要更好地了解侵蚀机制。 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 浅表糜烂中的细胞外陷阱（NET）。我们将在小鼠中使用经过验证的实验制剂 将受干扰的流动叠加在 GAG 和富含蛋白聚糖的内膜上，这是与人类斑块相关的条件 并发浅表糜烂，探讨此类血栓形成的分子和细胞机制 动脉粥样硬化的并发症。我的建议集中于 PMN 和 NET 功能的统一主题。 1）我们 将使用缺乏肽基精氨酸脱亚胺酶 4 (PAD4) 的小鼠来测试以下假设：在血流部位 具有糜烂样内膜的动脉紊乱，NETs 在局部内皮损伤和局部内皮损伤中发挥着重要作用 血栓形成。 2）我们将检验我们之前提出的骨髓相关蛋白（MRP）8/14的假设 与动脉疾病有关，导致局部 NETosis 以及内皮损伤和血栓形成 动脉血流紊乱，内膜糜烂。 3）我们检验了小鼠携带骨髓细胞的假设 细胞中的 V617F Jak2 变异与克隆造血和动脉粥样硬化风险增加相关 人类，会在血流紊乱部位加重 NETosis 和内皮损伤以及血栓形成 具有糜烂样内膜的动脉。这一目标不仅提供有关表面的机械信息 侵蚀，但将有助于阐明患有这种疾病的个体血栓事件增加的机制 体细胞突变常见于克隆性造血患者，这是一种新近认识到的潜在心血管风险 因素。我们的研究还将探索可立即转化为临床的新治疗策略。

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.