Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, 12 Wulumuqi Rd, Shanghai, 200040, China.
Department of Cardiology, Huashan Hospital of Fudan University, Shanghai, China.
J Nanobiotechnology. 2024 Nov 6;22(1):681. doi: 10.1186/s12951-024-02961-z.
Cardiovascular events secondary to stroke-collectively classified as stroke-heart syndrome-greatly impair the patient's prognosis, however its underlying mechanism has yet to be determined. To investigate the mechanism of central neuroinflammation and its effects on stroke-heart syndrome, a temperature-ultrasound responsive brain-targeted drug delivery system, DATS/MION-LPE, was synthesized to specifically study neuroinflammation in the mouse middle cerebral artery occlusion (MCAO) model.
The specific polymer of DATS/MION-LPE can close the nanoparticle pores at 37 °C, restricting drug release in the circulation. After the nanoparticles were targeted to brains, the polymer can be cleaved under external ultrasound irradiation, reopening the nanoparticle pores and allowing drug release, therefore directly managing the neuroinflammation. After a stroke, a significant cerebral inflammation occurred, with elevated IL-1β and pyrin domain-containing 3 (NLRP3) inflammasome. Accordingly, significantly increased histone deacetylase 6 (HDAC6) and decreased sirtuin 1 (SIRT1) were observed. An antagonistic relationship between HDAC6 and SIRT1 was found, which can jointly regulate the cerebral NLRP3 expression. The systemic IL-1β and ATP levels were increased after the stroke, accompanied by a significant heart injury including contractile dysfunction, elevated IL-1β levels, and oxidative stress. Meanwhile, neuroinflammation can trigger sympathetic nervous overexcitation with associated heart damage. DATS/MION-LPE can targetedly effect on ischemic brain, exhibiting cerebral and cardiac protective effects including downregulated cerebral NLRP3 and HDAC6 expressions, upregulated SIRT1 expressions in brain, reduced IL-1β and ATP in circulation, and alleviated cardiac impairment.
This study introduced the key role of neuroinflammation in stroke-heart syndrome and first investigated the crucial HDAC6/SIRT1-NLRP3 circuit in this process. Heart injury secondary to stroke is mediated by neuroinflammation induced systemic inflammatory responses and sympathoexcitation. DATS/MION-LPE is a unique tool and effective therapeutic agent, which provides new insights into combinational heart and cardiac protection.
中风引起的心血管事件——统称为中风-心脏综合征——极大地损害了患者的预后，但其潜在机制尚未确定。为了研究中枢神经炎症的机制及其对中风-心脏综合征的影响，我们合成了一种温度-超声响应的脑靶向药物递送系统 DATS/MION-LPE，以专门研究小鼠大脑中动脉闭塞（MCAO）模型中的神经炎症。
DATS/MION-LPE 的特定聚合物可以在 37°C 时关闭纳米颗粒的孔，限制循环中药物的释放。纳米颗粒靶向大脑后，聚合物可以在外源性超声辐射下被切割，重新打开纳米颗粒的孔并允许药物释放，从而直接控制神经炎症。中风后，大脑发生明显的炎症反应，IL-1β 和吡啶结构域包含 3（NLRP3）炎性小体升高。相应地，观察到组蛋白去乙酰化酶 6（HDAC6）显著增加和沉默调节蛋白 1（SIRT1）显著减少。发现 HDAC6 和 SIRT1 之间存在拮抗关系，它们可以共同调节大脑中的 NLRP3 表达。中风后全身 IL-1β 和 ATP 水平升高，伴有明显的心脏损伤，包括收缩功能障碍、IL-1β 水平升高和氧化应激。同时，神经炎症可引发交感神经过度兴奋，并伴有心脏损伤。DATS/MION-LPE 可以靶向缺血性大脑，表现出脑和心脏保护作用，包括大脑中 NLRP3 和 HDAC6 表达下调、SIRT1 表达上调、循环中 IL-1β 和 ATP 减少以及心脏损伤减轻。
本研究介绍了神经炎症在中风-心脏综合征中的关键作用，并首次研究了该过程中关键的 HDAC6/SIRT1-NLRP3 回路。中风引起的心脏损伤是由神经炎症引起的全身炎症反应和交感神经兴奋介导的。DATS/MION-LPE 是一种独特的工具和有效的治疗剂，为联合心脏和心脏保护提供了新的见解。
