Reduced Platelet miR-223 Induction in Kawasaki Disease Leads to Severe Coronary Artery Pathology Through a miR-223/PDGFRβ Vascular Smooth Muscle Cell Axis

作者：Yuan Zhang, Yanfei Wang, Li Zhang, Luoxing Xia, Minhui Zheng, Zhi Zeng, Yingying Liu, Timur O. Yarovinsky, Allison C. Ostriker, Xuejiao Fan, Kai Weng, Meiling Su, Ping Huang, Kathleen A. Martin, John Hwa, Wai Ho Tang · 发表于：Circulation Research · 年份：2020 · DOI：10.1161/circresaha.120.316951 · 被引用次数：79 · 研究领域：Kawasaki Disease and Coronary Complications、Autoimmune and Inflammatory Disorders Research、Vasculitis and related conditions

Rationale: 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. Objective: We set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD. Methods and Results: 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 PDGF...