线粒体靶向声动力调节神经炎症,防止心肌缺血再灌注损伤

Haoyuan Hu, Qian Li, Jiale Wang, Ye Cheng, Jiahui Zhao, Changhao Hu, Xinyue Yin, Yuzhe Wu, Ruiqi Sang, Hong Jiang, Yao Sun, Songyun Wang
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引用次数: 0

摘要

交感神经过度激活和炎症反应是心肌缺血再灌注(I/R)损伤和心肌I/R相关室性心律失常(VAs)的主要原因。先前的研究表明,发光二极管(LED)可以调节 I/R 后的神经炎症,从而为心肌 I/R 损伤提供保护。然而,由于发光二极管的穿透深度较低(小于 1 厘米)和潜在的光毒性,其进一步应用受到限制。低强度聚焦超声(LIFU)是一种新兴的无创神经调控策略,穿透深度更深(∼10 厘米),已被证实可以调节交感神经活动和炎症反应。声动力疗法(SDT)将 LIFU 与声敏化剂结合在一起,具有更多优势,包括卓越的疗效、神经元调节的精确定位和可忽略的副作用。本文引入 LIFU 和 SDT 来调节心肌 I/R 后的神经炎症,以保护心肌 I/R 损伤。结果表明,LIFU 和 SDT 可抑制交感神经活动,抑制星形胶质细胞和小胶质细胞的活化,促进小胶质细胞向 M2 表型极化,从而减轻心肌 I/R 损伤,预防 I/R 相关的恶性 VA。这些研究结果表明,LIFU 和 SDT 是一种无创、高效的神经炎症调节策略,具有巨大的临床转化潜力,未来将造福更多的心肌 I/R 患者。意义声明:心肌缺血再灌注(I/R)可能导致 I/R 损伤和 I/R 诱导的室性心律失常。交感神经过度激活和炎症反应在心肌缺血再灌注损伤中起着不利作用。以往的研究表明,发光二极管(LED)可以调节 I/R 诱导的神经炎症,从而起到保护心肌的作用。然而,由于发光二极管的穿透深度低且具有潜在光毒性,因此很难实现临床转化。在此,我们基于线粒体靶向纳米声纳敏化剂(CCNU980 NPs),引入了声动力调节神经炎症以保护心肌I/R损伤。我们证实,声动力调节可促进小胶质细胞自噬,从而预防心肌I/R损伤和I/R诱发的室性心律失常。这是声波动力学调节心肌I/R诱导的神经炎症的首个实例,为临床转化提供了一种新策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mitochondria-targeted sonodynamic modulation of neuroinflammation to protect against myocardial ischemia‒reperfusion injury.

Sympathetic hyperactivation and inflammatory responses are the main causes of myocardial ischemia‒reperfusion (I/R) injury and myocardial I/R-related ventricular arrhythmias (VAs). Previous studies have demonstrated that light-emitting diodes (LEDs) could modulate post-I/R neuroinflammation, thus providing protection against myocardial I/R injury. Nevertheless, further applications of LEDs are constrained due to the low penetration depth (<1 cm) and potential phototoxicity. Low-intensity focused ultrasound (LIFU), an emerging noninvasive neuromodulation strategy with deeper penetration depth (∼10 cm), has been confirmed to modulate sympathetic nerve activity and inflammatory responses. Sonodynamic therapy (SDT), which combines LIFU with sonosensitizers, confers additional advantages, including superior therapeutic efficacy, precise localization of neuronal modulation and negligible side effects. Herein, LIFU and SDT were introduced to modulate post-myocardial I/R neuroinflammation to protect against myocardial I/R injury. The results indicated that LIFU and SDT inhibited sympathetic neural activity, suppressed the activation of astrocytes and microglia, and promoted microglial polarization towards the M2 phenotype, thereby attenuating myocardial I/R injury and preventing I/R-related malignant VAs. These insights suggest that LIFU and SDT inspire a noninvasive and efficient neuroinflammatory modulation strategy with great clinical translation potential thus benefiting more patients with myocardial I/R in the future. STATEMENT OF SIGNIFICANCE: Myocardial ischemia-reperfusion (I/R) may cause I/R injury and I/R-induced ventricular arrhythmias. Sympathetic hyperactivation and inflammatory response play an adverse effect in myocardial I/R injury. Previous studies have shown that light emitting diode (LED) can regulate I/R-induced neuroinflammation, thus playing a myocardial protective role. However, due to the low penetration depth and potential phototoxicity of LED, it is difficult to achieve clinical translation. Herein, we introduced sonodynamic modulation of neuroinflammation to protect against myocardial I/R injury, based on mitochondria-targeted nanosonosensitizers (CCNU980 NPs). We demonstrated that sonodynamic modulation could promote microglial autophagy, thereby preventing myocardial I/R injury and I/R-induced ventricular arrhythmias. This is the first example of sonodynamic modulation of myocardial I/R-induced neuroinflammation, providing a novel strategy for clinical translation.

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