Reduced Platelet miR-223 Induction in Kawasaki Disease Leads To Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell Axis.
Reduced Platelet miR-223 Induction in Kawasaki Disease Leads To Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell Axis.
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川崎病中血小板 miR-223 诱导减少通过 miR-223/PDGFRβ 血管平滑肌细胞轴导致严重的冠状动脉病理学。
DOI：
10.1161/circresaha.120.316951
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发表时间：
2020
影响因子：
20.1
通讯作者：
Tang Wai Ho
中科院分区：
文献类型：
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作者：
Zhang Yuan;Wang Yanfei;Zhang Li;Xia Luoxing;Zheng Min Hui;Zeng Zhi;Liu Ying-Ying;Yarovinsky Timur O;Ostriker Allison C;Fan Xuejiao;Weng Kai;Su Meiling;Huang Ping;Martin Kathleen A;Hwa John;Tang Wai Ho
川崎病（KD）是一种发生在儿童早期的急性血管炎，可导致永久性冠状动脉结构损伤。高达15%的KD患者动脉脆弱性的原因尚不清楚。血管平滑肌细胞去分化在中膜损伤和动脉瘤形成的病理生理学中起关键作用，这是公认的KD动脉病理学。血小板高反应性也是KD的标志。我们最近表明，血小板和血小板衍生的miRNA的摄取影响血管平滑肌细胞的表型在vivo. ESTA我们着手探讨血小板/血管平滑肌细胞（VSMC）的相互作用是否有助于冠状动脉病变在KD.Methods和ResultsWe前瞻性招募和研究了242例KD，其中75人有记录的冠状动脉病变。全基因组miRNA测序和液滴数字PCR证实，与健康对照（HC）相比，KD血小板患者具有显著的miR-223诱导。最近已显示血小板衍生的miR-223促进血管平滑肌静止和血管损伤后伤口愈合的消退。奇怪的是，具有最严重冠状动脉病理（巨大冠状动脉瘤）的KD患者表现出缺乏miR-223诱导。从KD患者中分离的过度活跃的血小板容易被VSMC摄取，将功能性miR-223递送到VSMC中，通过下调PDGFRβ（血小板衍生生长因子受体β）促进VSMC分化。严重冠状动脉病变患者中缺乏miR-223诱导导致持续的VSMC去分化。在KD（干酪乳杆菌细胞壁提取物注射）小鼠模型中，与WT小鼠相比，miR-223敲除小鼠表现出中膜增厚增加，中膜中收缩性VSMC丢失，以及中膜弹性纤维断裂，这表明在干酪乳杆菌细胞壁提取物激发时miR-223显著诱导。miR-223敲除后的过度动脉损伤可通过血小板过继转移、miR-223模拟物给药或PDGFRβ抑制剂甲磺酸伊马替尼来挽救。有趣的是，miR-223水平随着年龄的增长而逐渐增加，在<5岁的儿童中发现最低水平。结论血小板源性miR-223（通过PDGFRβ抑制）促进VSMC分化和KD诱导的血管损伤的消退。缺乏miR-223诱导导致以VSMC去分化和中膜损伤为特征的严重冠状动脉病理学。在KD患者中检测血小板源性miR-223（诊断时）可识别冠状动脉病变风险最大的患者。此外，靶向血小板miR-223或VSMC PDGFRβ是缓解KD冠状动脉病变的潜在治疗策略。
RationaleKawasaki disease (KD) is an acute vasculitis of early childhood that can result in permanent coronary artery structural damage. The cause for this arterial vulnerability in up to 15% of patients with KD is unknown. Vascular smooth muscle cell dedifferentiation play a key role in the pathophysiology of medial damage and aneurysm formation, recognized arterial pathology in KD. Platelet hyperreactivity is also a hallmark of KD. We recently demonstrated that uptake of platelets and platelet-derived miRNAs influences vascular smooth muscle cell phenotype in vivo.ObjectiveWe set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD.Methods and ResultsWe prospectively recruited and studied 242 patients with KD, 75 of whom had documented coronary artery pathology. Genome-wide miRNA sequencing and droplet digital PCR demonstrated that patient with KD platelets have significant induction of miR-223 compared with healthy controls (HCs). Platelet-derived miR-223 has recently been shown to promote vascular smooth muscle quiescence and resolution of wound healing after vessel injury. Paradoxically, patients with KD with the most severe coronary pathology (giant coronary artery aneurysms) exhibited a lack of miR-223 induction. Hyperactive platelets isolated from patients with KD are readily taken up by VSMCs, delivering functional miR-223 into the VSMCs promoting VSMC differentiation via downregulation of PDGFRβ (platelet-derived growth factor receptor β). The lack of miR-223 induction in patients with severe coronary pathology leads to persistent VSMC dedifferentiation. In a mouse model of KD (Lactobacillus caseicell wall extract injection), miR-223 knockout mice exhibited increased medial thickening, loss of contractile VSMCs in the media, and fragmentation of medial elastic fibers compared with WT mice, which demonstrated significant miR-223 induction uponLactobacillus caseicell wall extract challenge. The excessive arterial damage in the miR-223 knockout could be rescued by adoptive transfer of platelet, administration of miR-223 mimics, or the PDGFRβ inhibitor imatinib mesylate. Interestingly, miR-223 levels progressively increase with age, with the lowest levels found in <5-year-old. This provides a basis for coronary pathology susceptibility in this very young cohort.ConclusionsPlatelet-derived miR-223 (through PDGFRβ inhibition) promotes VSMC differentiation and resolution of KD induced vascular injury. Lack of miR-223 induction leads to severe coronary pathology characterized by VSMC dedifferentiation and medial damage. Detection of platelet-derived miR-223 in patients with KD (at the time of diagnosis) may identify patients at greatest risk of coronary artery pathology. Moreover, targeting platelet miR-223 or VSMC PDGFRβ represents potential therapeutic strategies to alleviate coronary pathology in KD.Graphic AbstractA graphic abstract is available for this article.