BACKGROUND:Heart failure is associated with a high rate of mortality and morbidity, and ventricular remodeling invariably precedes heart failure. Ventricular remodeling is fundamentally driven by mechanotransduction that is regulated by both the nervous system and the immune system. However, it remains unknown which key molecular factors govern the neuro/immune/cardio axis that underlies mechanotransduction during ventricular remodeling. Here, we investigated whether the mechanosensitive Piezo cation channel–mediated neurogenic inflammatory cascade underlies ventricular remodeling–related mechanotransduction.METHODS:By ligating the left coronary artery of rats to establish an in vivo model of chronic myocardial infarction (MI), lentivirus-mediated thoracic dorsal root ganglion (TDRG)–specific Piezo1 knockdown rats and adeno-associated virus–PHP.S—mediated TDRG neuron–specific Piezo1 knockout mice were used to investigate whether Piezo1 in the TDRG plays a functional role during ventricular remodeling Subsequently, neutralizing antibody–mediated TDRG IL-6 (interleukin-6) inhibition rats and adeno-associated virus–PHP.S—mediated TDRG neuron–specific IL-6 knockdown mice were used to determine the mechanism underlying neurogenic inflammation. Primary TDRG neurons were used to evaluate Piezo1 function in vitro.RESULTS:Expression of Piezo1 and IL-6 was increased, and these factors were functionally activated in TDRG neurons at 4 weeks after MI. Both knockdown of TDRG-specific Piezo1 and deletion of TDRG neuron–specific Piezo1 lessened the severity of ventricular remodeling at 4 weeks after MI and decreased the level of IL-6 in the TDRG or heart. Furthermore, inhibition of TDRG IL-6 or knockdown of TDRG neuron–specific IL-6 also ameliorated ventricular remodeling and suppressed the IL-6 cascade in the heart, whereas the Piezo1 level in the TDRG was not affected. In addition, enhanced Piezo1 function, as reflected by abundant calcium influx induced by Yoda1 (a selective agonist of Piezo1), led to increased release of IL-6 from TDRG neurons in mice 4 weeks after MI.CONCLUSIONS:Our findings point to a critical role for Piezo1 in ventricular remodeling at 4 weeks after MI and reveal a neurogenic inflammatory cascade as a previously unknown facet of the neuronal immune signaling axis underlying mechanotransduction.

中文翻译：

---

Piezo1 介导的神经源性炎症级联加剧心肌梗死后的心室重塑

背景：心力衰竭与高死亡率和发病率相关，心室重构总是先于心力衰竭。心室重塑从根本上是由神经系统和免疫系统调节的机械转导驱动的。然而，目前尚不清楚哪些关键分子因素控制神经/免疫/心脏轴，而神经/免疫/心脏轴是心室重塑过程中机械转导的基础。在这里，我们研究了机械敏感性压电阳离子通道介导的神经源性炎症级联是否是心室重塑相关机械转导的基础。方法：通过结扎大鼠左冠状动脉建立慢性心肌梗死（MI）体内模型，慢病毒介导的胸腔使用背根神经节（TDRG）特异性 Piezo1 敲除大鼠和腺相关病毒 -PHP.S 介导的 TDRG 神经元特异性 Piezo1 敲除小鼠来研究 TDRG 中的 Piezo1 在心室重塑过程中是否发挥功能作用随后，中和抗体 -介导的 TDRG IL-6（白细胞介素 6）抑制大鼠和腺相关病毒 PHP.S 介导的 TDRG 神经元特异性 IL-6 敲低小鼠用于确定神经源性炎症的机制。采用原代TDRG神经元体外评价Piezo1功能。结果：MI后4周TDRG神经元中Piezo1和IL-6的表达增加，且这些因子在功能上被激活。TDRG 特异性 Piezo1 的敲低和 TDRG 神经元特异性 Piezo1 的缺失均减轻了 MI 后 4 周心室重构的严重程度，并降低了 TDRG 或心脏中 IL-6 的水平。此外，抑制 TDRG IL-6 或敲除 TDRG 神经元特异性 IL-6 也可改善心室重塑并抑制心脏中的 IL-6 级联，而 TDRG 中的 Piezo1 水平不受影响。此外，Yoda1（Piezo1 的选择性激动剂）诱导的大量钙离子流入反映了 Piezo1 功能的增强，导致 MI 后 4 周小鼠 TDRG 神经元中 IL-6 的释放增加。 结论：我们的研究结果指出了一个关键因素研究人员研究了 Piezo1 在 MI 后 4 周心室重塑中的作用，并揭示了神经源性炎症级联反应是机械转导神经元免疫信号轴的一个先前未知的方面。