From the Institute of Pediatrics (Y.Z., L.X., M.Z., Z.Z., Y.L., X.F., K.W., M.S., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, China.
Department of Cardiology (Y.W., L.Z., P.H.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, China.
Circ Res. 2020 Sep 11;127(7):855-873. doi: 10.1161/CIRCRESAHA.120.316951. Epub 2020 Jun 29.
Kawasaki 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.
We set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD.
We 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 ( cell 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 upon cell 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.
Platelet-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 Abstract: A graphic abstract is available for this article.
川崎病（KD）是一种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 患者的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 KD 的公认的动脉病理学。血小板高反应性也是 KD 的一个标志。我们最近证明，血小板和血小板衍生的 miRNA 的摄取会影响体内血管平滑肌细胞表型。
我们旨在探讨血小板/血管平滑肌细胞（VSMC）相互作用是否导致 KD 的冠状动脉病理学。
我们前瞻性地招募并研究了 242 名 KD 患者，其中 75 名患者有明确的冠状动脉病理学。全基因组 miRNA 测序和液滴数字 PCR 表明，KD 患者的血小板与健康对照组（HCs）相比，miR-223 的诱导显著增加。血小板衍生的 miR-223 最近被证明可促进血管平滑肌静止和血管损伤后伤口愈合的消退。矛盾的是，KD 患者中冠状动脉病理学最严重（巨大冠状动脉瘤）的患者表现出缺乏 miR-223 的诱导。从 KD 患者中分离出的高活性血小板很容易被 VSMC 摄取，通过下调 PDGFRβ（血小板衍生生长因子受体β）将功能性 miR-223 递送到 VSMC 中，促进 VSMC 分化。严重冠状动脉病理学患者中缺乏 miR-223 的诱导导致 VSMC 持续去分化。在 KD 的小鼠模型（细胞壁提取物注射）中，与 WT 小鼠相比，miR-223 敲除小鼠表现出中膜增厚增加、中膜收缩型 VSMC 丢失和中膜弹性纤维碎裂，而 WT 小鼠在细胞壁提取物挑战时表现出显著的 miR-223 诱导。miR-223 敲除小鼠的过度动脉损伤可以通过血小板的过继转移、miR-223 模拟物的给药或 PDGFRβ 抑制剂伊马替尼来挽救。有趣的是，miR-223 水平随年龄逐渐增加，在<5 岁时最低。这为该非常年轻的队列中的冠状动脉病理学易感性提供了依据。
血小板衍生的 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 的诱导会导致严重的冠状动脉病理学，其特征是 VSMC 去分化和中膜损伤。在 KD 患者（诊断时）检测血小板衍生的 miR-223 可能会识别出发生冠状动脉病理学风险最大的患者。此外，靶向血小板 miR-223 或 VSMC PDGFRβ 可能是减轻 KD 冠状动脉病理学的潜在治疗策略。
