Novel mechanisms of the thrombotic complications of atherosclerosis

目前的临床和病理学数据表明， 血栓并发症的人类动脉粥样硬化。人体斑块含有较少的脂质和 巨噬细胞的作用。急性冠状动脉综合征（ACS）患者包括更多、更年轻的 女性、肥胖和胰岛素抵抗个体。ST段抬高型心肌梗死（STEMI） 随着非STEMI的上升而下降。我们已经收集了ACS机制转变的证据。 在当前的低密度脂蛋白（LDL）浓度降低的时代，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，而浅表糜烂作为ACS的比例正在增加。虽然我们 对斑块破裂的生物学基础以及脂质- 降低可以减弱血栓形成的触发，关于机制的知识缺口很大 表面腐蚀的痕迹这一过程与斑块破裂有很大不同： 引起的糜烂通常缺乏明显的脂质聚集，有很少的巨噬细胞和更多的蛋白聚糖 和糖胺聚糖（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，侵蚀引起的ACS的管理不需要紧急侵入性 治疗，使寻求更好地了解腐蚀的机制，医学上势在必行。 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 细胞外陷阱（NET）在浅表糜烂。我们将在小鼠中使用经过验证的实验制剂， 在GAG和富含蛋白多糖的内膜上叠加干扰流，这是属于人类斑块的条件 复杂的表面侵蚀，以探测这种类型的血栓形成的分子和细胞机制， 动脉粥样硬化并发症。我的建议集中在PMN和NET函数的统一主题上。1)我们 将使用缺乏肽基精氨酸脱亚胺酶4（PAD 4）的小鼠来测试以下假设： 在动脉中具有侵蚀样内膜的紊乱，NET严重参与局部内皮损伤， 血栓形成2)我们将测试假设，骨髓相关蛋白（MRP）8/14，我们以前已经 涉及动脉疾病，导致局部NETosis和内皮损伤和血栓形成， 动脉血流紊乱伴内膜糜烂。3)我们检验了一个假设， V617 F Jak 2变异体与克隆性造血相关，并增加了动脉粥样硬化的风险。 人类，将加重NETosis和内皮损伤，并在血流障碍部位形成血栓， 动脉内膜糜烂。这一目标不仅将提供关于表面的机械信息， 侵蚀，但将有助于阐明机制增加血栓事件的个人谁承担这一点 克隆性造血中常见的体细胞突变，一种新认识到的潜在心血管风险 因子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.