Rationale:
Kawasaki disease (KD) is an acute vasculitis of early childhood that can result in per-manent coronary artery structural damage. The etiology for this arterial vulnerability in up to 15% of KD patients is unknown. Vascular smooth muscle cell (VSMC) 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 VSMC phenotype in vivo.
Objective:
We set out to explore whether platelet/vascular smooth muscle cell interactions contrib-ute to coronary pathology in KD.
Methods and Results:
We prospectively recruited and studied 242 KD patients, 75 of whom had doc-umented coronary artery pathology. Genome-wide miRNA sequencing and droplet digital PCR (ddPCR) demonstrated that KD patient platelets have significant induction of miR-223 compared to healthy controls. Platelet-derived miR-223 has recently been shown to promote vascular smooth muscle quiescence and resolution of wound healing after vessel injury. Paradoxically, KD patients with the most severe coronary pathology (giant coronary artery aneurysms) exhibited a lack of miR-223 induction. Hyperactive platelets isolated from KD patients are readily taken up by VSMCs, delivering functional miR-223 into the VSMCs promoting VSMC differentiation via downregulation of platelet-derived growth factor receptor β (PDGFRβ). The lack of miR-223 induction in patients with severe coronary pathology leads to persistent VSMC dedifferentiation. In a mouse model of KD (Lactobacillus casei cell wall extract (LCWE) injection), miR-223 knockout (miR-223 KO) mice exhibited increased medial thickening, loss of contractile VSMCs in the media, and fragmenta-tion of medial elastic fibers compared to WT mice, which demonstrated significant miR-223 induc-tion upon LCWE challenge. The excessive arterial damage in the miR-223 knockout could be res-cued 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 less than five-year-old. This provides a basis for coronary pathology susceptibility in this very young cohort.
Conclusions:
Platelet-derived miR-223 (through PDGFRβ inhibition) promotes VSMC differentia-tion and resolution of KD induced vascular injury. Lack of miR-223 induction leads to severe coro-nary pathology characterized by VSMC dedifferentiation and medial damage. Detection of platelet-derived miR-223 in KD patients (at the time of diagnosis) may identify patients at greatest risk of coronary artery pathology. Moreover, targeting platelet miR-223 or VSMC PDGFRβ represents po-tential therapeutic strategies to alleviate coronary pathology in KD.
These data suggest that androgen therapy could play an important role in pathophysiological changes in heart failure and have beneficial effects for its treatment.
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