Aims CD4+ T cells are activated during inflammatory dilated cardiomyopathy (iDCM) development to induce immunogenic responses that damage the myocardium. Low-intensity pulsed ultrasound (LIPUS), a novel physiotherapy for cardiovascular diseases, has recently been shown to modulate inflammatory responses. However, its efficacy in iDCM remains unknown. Here, we investigated whether LIPUS could improve the severity of iDCM by orchestrating immune responses and explored its therapeutic mechanisms. Methods and results In iDCM mice, LIPUS treatment reduced cardiac remodelling and dysfunction. Additionally, CD4+ T cell inflammatory responses were suppressed. LIPUS increased Treg cells while decreasing Th17 cells. LIPUS mechanically stimulates endothelial cells, resulting in increased secretion of extracellular vesicles (EVs), which are taken up by CD4+ T cells and alter their differentiation and metabolic patterns. Moreover, EVs selectively loaded with microRNA (miR)-99a are responsible for the therapeutic effects of LIPUS. The hnRNPA2B1 translocation from the nucleus to the cytoplasm and binding to caveolin-1 and miR-99a confirmed the upstream mechanism of miR-99a transport. This complex is loaded into EVs and taken up by CD4+ T cells, which further suppress mTOR and TRIB2 expression to modulate cellular differentiation. Conclusion Our findings revealed that LIPUS uses an EV-dependent molecular mechanism to protect against iDCM progression. Therefore, LIPUS is a promising new treatment option for iDCM.

中文翻译：

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低强度脉冲超声通过刺激细胞外囊泡预防炎症扩张型心肌病

目的 CD4+ T 细胞在炎症性扩张型心肌病 (iDCM) 发展过程中被激活，诱导损害心肌的免疫原性反应。低强度脉冲超声（LIPUS）是一种治疗心血管疾病的新型物理疗法，最近被证明可以调节炎症反应。然而，其在 iDCM 中的功效仍然未知。在这里，我们研究了 LIPUS 是否可以通过协调免疫反应来改善 iDCM 的严重程度，并探讨其治疗机制。方法和结果 在 iDCM 小鼠中，LIPUS 治疗减少了心脏重塑和功能障碍。此外，CD4+ T 细胞炎症反应也受到抑制。 LIPUS 增加了 Treg 细胞，同时减少了 Th17 细胞。 LIPUS 机械刺激内皮细胞，导致细胞外囊泡 (EV) 的分泌增加，这些囊泡被 CD4+ T 细胞吸收并改变其分化和代谢模式。此外，选择性加载 microRNA (miR)-99a 的 EV 是 LIPUS 的治疗效果的原因。 hnRNPA2B1从细胞核易位到细胞质并与caveolin-1和miR-99a结合证实了miR-99a转运的上游机制。该复合物被加载到 EV 中并被 CD4+ T 细胞吸收，进一步抑制 mTOR 和 TRIB2 表达以调节细胞分化。结论 我们的研究结果表明，LIPUS 使用 EV 依赖性分子机制来防止 iDCM 进展。因此，LIPUS是一种有前景的iDCM新治疗选择。