Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
Department of Haematology, UCL Cancer Institute, London, UK; Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Int J Cardiol. 2024 Aug 15;409:132184. doi: 10.1016/j.ijcard.2024.132184. Epub 2024 May 16.
Superficial plaque erosion causes many acute coronary syndromes. However, mechanisms of plaque erosion remain poorly understood, and we lack directed therapeutics for thrombotic complication. Human eroded plaques can harbor neutrophil extracellular traps (NETs) that propagate endothelial damage at experimental arterial lesions that recapitulate superficial erosion. Clonal Hematopoiesis of Indeterminate Potential (CHIP) denotes age-related clonal expansion of bone marrow-derived cells harboring somatic mutations in the absence of overt hematological disease. CHIP heightens the risk of cardiovascular disease, with the greatest increase seen in individuals with JAK2. Neutrophils from mice and humans with JAK2 undergo NETosis more readily than Jak2 (wild-type) cells. We hypothesized that JAK2, by increasing propensity to NETosis, exacerbates aspects of superficial erosion.
We generated Jak2 and Jak2 mice with heterozygous Jak2 in myeloid cells. We induced areas of denuded endothelium that recapitulate features of superficial erosion and assessed endothelial integrity, cellular composition of the erosion, thrombosis rates, and response to ruxolitinib, a clinically available JAK1/2 inhibitor, in relation to genotype. Following experimental erosion, Jak2 mice have greater impairment of endothelial barrier function and increased rates of arterial thrombosis. Neointimas in Jak2 mice exhibit increased apoptosis, NETosis, and platelet recruitment. Jak2 mice treated with ruxolitinib show increased endothelial continuity and reduced apoptosis in the neointima comparable to levels in Jak2.
These observations provide new mechanistic insight into the pathophysiology of superficial erosion, the heightened risk for myocardial infarction in JAK2 CHIP, and point the way to personalized therapeutics based on CHIP status.
浅层斑块侵蚀可引发许多急性冠脉综合征。然而，斑块侵蚀的机制仍知之甚少，且我们缺乏针对血栓并发症的靶向治疗。人类侵蚀斑块中可能存在中性粒细胞胞外诱捕网（NETs），这些 NETs 在实验性动脉病变中可加剧内皮损伤，从而模拟浅层侵蚀。不确定潜能的克隆性造血（CHIP）表示骨髓源性细胞的年龄相关克隆性扩张，这些细胞在没有明显血液疾病的情况下存在体细胞突变。CHIP 会增加心血管疾病的风险，在 JAK2 个体中风险增加最大。与 Jak2（野生型）细胞相比，具有 JAK2 的小鼠和人类的中性粒细胞更容易发生 NETosis。我们假设 JAK2 通过增加 NETosis 的倾向，加剧了浅层侵蚀的某些方面。
我们生成了具有髓样细胞中杂合性 Jak2 的 Jak2 和 Jak2 小鼠。我们诱导了重现浅层侵蚀特征的裸露内皮区域，并评估了内皮完整性、侵蚀的细胞组成、血栓形成率以及与基因型相关的对鲁索替尼（一种临床可用的 JAK1/2 抑制剂）的反应。在实验性侵蚀后，Jak2 小鼠的内皮屏障功能受损更大，动脉血栓形成率增加。Jak2 小鼠的新生内膜中凋亡、NETosis 和血小板募集增加。用鲁索替尼治疗的 Jak2 小鼠表现出内皮连续性增加和新生内膜中凋亡减少，与 Jak2 水平相当。
这些观察结果为浅层侵蚀的病理生理学、JAK2 CHIP 中心肌梗死风险增加提供了新的机制见解，并为基于 CHIP 状态的个体化治疗指明了方向。
