Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Road, Nan Gang Dist., Harbin, 150086, Heilongjiang Province, China.
Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang Province, No. 246 XueFu Road, Nan Gang Dist, Harbin, 150086, Heilongjiang Province, China.
Cardiovasc Res. 2024 Sep 2;120(10):1177-1190. doi: 10.1093/cvr/cvae096.
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.
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.
Our findings revealed that LIPUS uses an EVs-dependent molecular mechanism to protect against iDCM progression. Therefore, LIPUS is a promising new treatment option for iDCM.
CD4+T 细胞在炎症性扩张型心肌病（iDCM）发展过程中被激活，以引发免疫原性反应，从而损害心肌。低强度脉冲超声（LIPUS）是一种心血管疾病的新型物理疗法，最近已被证明可调节炎症反应。然而，其在 iDCM 中的疗效尚不清楚。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，并探讨了其治疗机制。
在 iDCM 小鼠中，LIPUS 治疗可减轻心脏重构和功能障碍。此外，CD4+T 细胞炎症反应受到抑制。LIPUS 增加了 Treg 细胞，同时减少了 Th17 细胞。LIPUS 通过机械刺激内皮细胞，导致细胞外囊泡（EVs）的分泌增加，EVs 被 CD4+T 细胞摄取，并改变其分化和代谢模式。此外，EVs 选择性地装载 microRNA（miR）-99a，是 LIPUS 治疗效果的关键。hnRNPA2B1 从核内易位到细胞质，并与 caveolin-1 和 miR-99a 结合，证实了 miR-99a 运输的上游机制。该复合物被加载到 EVs 中并被 CD4+T 细胞摄取，进一步抑制 mTOR 和 TRIB2 的表达，从而调节细胞分化。
我们的研究结果表明，LIPUS 利用 EVs 依赖的分子机制来防止 iDCM 的进展。因此，LIPUS 是治疗 iDCM 的一种有前途的新方法。
