Crystal Clots as Therapeutic Target in Cholesterol Crystal Embolism
Crystal Clots as Therapeutic Target in Cholesterol Crystal Embolism
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DOI：
10.1161/circresaha.119.315625
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发表时间：
2020-04-10
影响因子：
20.1
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Shi, Chongxu;Kim, Tehyung;Anders, Hans-Joachim
理论基础：胆固醇晶体栓塞可能是晚期动脉粥样硬化的一种危及生命的并发症。目的：建立一种新的胆固醇晶体栓塞动物模型，以探讨胆固醇晶体导致动脉闭塞、组织梗塞和器官衰竭的分子机制。方法和结果：C57BL/6J小鼠左肾动脉注射胆固醇晶体。主要终点为肾小球滤过率(GFR)。CC导致肾内动脉结晶体凝块闭塞，GFR呈剂量依赖性下降，随后GFR在4周内恢复，即急性肾病。相比之下，肾梗死的程度更具变异性。使用混合谱系激酶结构域缺陷小鼠或Necrostatin-1s治疗来阻止坏死性下垂可防止肾梗死，但不能防止GFR丢失，因为动脉阻塞持续存在，确定晶体凝块是预防器官衰竭的主要靶点。CC涉及血小板、中性粒细胞、纤维蛋白和细胞外DNA。去除中性粒细胞或抑制中性粒细胞胞外陷阱的释放几乎没有效果，但用氯吡格雷拮抗血小板P2Y12受体，用尿激酶溶解纤溶蛋白，或用重组DNase I消化DNA，都能预防动脉闭塞、GFR丢失和肾梗死。机会之窗是
Rationale:Cholesterol crystal embolism can be a life-threatening complication of advanced atherosclerosis. Pathophysiology and molecular targets for treatment are largely unknown.Objective:We aimed to develop a new animal model of cholesterol crystal embolism to dissect the molecular mechanisms of cholesterol crystal (CC)-driven arterial occlusion, tissue infarction, and organ failure.Methods and Results:C57BL/6J mice were injected with CC into the left kidney artery. Primary end point was glomerular filtration rate (GFR). CC caused crystal clots occluding intrarenal arteries and a dose-dependent drop in GFR, followed by GFR recovery within 4 weeks, that is, acute kidney disease. In contrast, the extent of kidney infarction was more variable. Blocking necroptosis using mixed lineage kinase domain-like deficient mice or necrostatin-1s treatment protected from kidney infarction but not from GFR loss because arterial obstructions persisted, identifying crystal clots as a primary target to prevent organ failure. CC involved platelets, neutrophils, fibrin, and extracellular DNA. Neutrophil depletion or inhibition of the release of neutrophil extracellular traps had little effects, but platelet P2Y12 receptor antagonism with clopidogrel, fibrinolysis with urokinase, or DNA digestion with recombinant DNase I all prevented arterial occlusions, GFR loss, and kidney infarction. The window-of-opportunity was