Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile; Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile.
Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile.
EBioMedicine. 2022 Jun;80:104044. doi: 10.1016/j.ebiom.2022.104044. Epub 2022 May 9.
Breathing disorders (BD) (apnoeas/hypopneas, periodic breathing) are highly prevalent in chronic heart failure (CHF) and are associated with altered central respiratory control. Ample evidence identifies the retrotrapezoid nucleus (RTN) as an important chemosensitivity region for ventilatory control and generation of BD in CHF, however little is known about the cellular mechanisms underlying the RTN/BD relationship. Within the RTN, astrocyte-mediated purinergic signalling modulates respiration, but the potential contribution of RTN astrocytes to BD in CHF has not been explored.
Selective neuron and/or astrocyte-targeted interventions using either optogenetic and chemogenetic manipulations in the RTN of CHF rats were used to unveil the contribution of the RTN on the development/maintenance of BD, the role played by astrocytes in BD and the molecular mechanism underpinning these alterations.
We showed that episodic photo-stimulation of RTN neurons triggered BD in healthy rats, and that RTN neurons ablation in CHF animals eliminates BD. Also, we found a reduction in astrocytes activity and ATP bioavailability within the RTN of CHF rats, and that chemogenetic restoration of normal RTN astrocyte activity and ATP levels improved breathing regularity in CHF. Importantly, P"X/ P2X7 receptor (P2X7r) expression was reduced in RTN astrocytes from CHF rats and viral vector-mediated delivery of human P2X7 P2X7r into astrocytes increases ATP bioavailability and abolished BD.
Our results support that RTN astrocytes play a pivotal role on BD generation and maintenance in the setting CHF by a mechanism encompassing P2X7r signalling.
This study was funded by the National Research and Development Agency of Chile (ANID).
呼吸障碍（BD）（呼吸暂停/低通气、周期性呼吸）在慢性心力衰竭（CHF）中非常普遍，与中枢呼吸控制改变有关。大量证据表明，梯形核后区（RTN）是呼吸控制和 CHF 中 BD 产生的重要化学敏感性区域，然而，关于 RTN/BD 关系的细胞机制知之甚少。在 RTN 内，星形胶质细胞介导的嘌呤能信号调节呼吸，但 RTN 星形胶质细胞对 CHF 中 BD 的潜在贡献尚未得到探索。
在 CHF 大鼠的 RTN 中使用光遗传学和化学遗传学操作对选择性神经元和/或星形胶质细胞靶向干预，以揭示 RTN 对 BD 发展/维持的贡献、星形胶质细胞在 BD 中的作用以及这些改变的潜在分子机制。
我们表明，RTN 神经元的间歇性光刺激会在健康大鼠中引发 BD，而 CHF 动物中 RTN 神经元的消融会消除 BD。此外，我们发现 CHF 大鼠 RTN 内星形胶质细胞活性和 ATP 生物利用度降低，并且化学遗传学恢复正常 RTN 星形胶质细胞活性和 ATP 水平可改善 CHF 中的呼吸规律性。重要的是，CHF 大鼠 RTN 星形胶质细胞中的 P"X/ P2X7 受体（P2X7r）表达减少，而病毒载体介导的人 P2X7 P2X7r 递送至星形胶质细胞可增加 ATP 生物利用度并消除 BD。
我们的结果支持 RTN 星形胶质细胞通过包含 P2X7r 信号的机制在 CHF 中对 BD 的产生和维持起着关键作用。
本研究由智利国家研究与开发机构（ANID）资助。
