PDF(Pubmed)
Abstract：
BACKGROUND: Elevated inflammatory cytokines in the periphery have been identified as active contributors to neuroinflammation and sympathetic overactivity in heart failure (HF). Yet, the exact mechanisms by which these cytokines breach the blood-brain barrier (BBB) to exert their effects on the brain remain elusive. Interleukin 17A has been linked to BBB disruption in various neurologic disorders, and its levels were significantly augmented in circulation and the brain in HF. The present study aimed to determine whether the BBB integrity was compromised within the hypothalamic paraventricular nucleus (PVN), and if so, whether interleukin 17A contributes to BBB disruption in myocardial infarction-induced HF.
RESULTS: Male Sprague-Dawley rats underwent coronary artery ligation to induce HF or sham surgery. Some HF rats received bilateral PVN microinjections of an interleukin 17 receptor A small interfering RNA or a scrambled small interfering RNA adeno-associated virus. Four weeks after coronary artery ligation, the permeability of the BBB was evaluated by intracarotid injection of fluorescent dyes (fluorescein isothiocyanate-dextran 10 kDa+rhodamine-dextran 70 kDa). Compared with sham-operated rats, HF rats exhibited an elevated extravasation of fluorescein isothiocyanate-dextran 10 kDa within the PVN but not in the brain cortex. The plasma interleukin 17A levels were positively correlated with fluorescein isothiocyanate 10 kDa extravasation in the PVN. The expression of caveolin-1, a transcytosis marker, was augmented, whereas the expression of tight junction proteins was diminished in HF rats. Interleukin 17 receptor A was identified within the endothelium of PVN microvessels. Treatment with interleukin 17 receptor A small interfering RNA led to a significant attenuation of fluorescein isothiocyanate 10 kDa extravasation in the PVN and reversed expression of caveolin-1 and tight junction-associated proteins in the PVN.
CONCLUSIONS: Collectively, these data indicate that BBB permeability within the PVN is enhanced in HF and is likely attributable to increased interleukin 17A/interleukin 17 receptor A signaling in the BBB endothelium, by promoting caveolar transcytosis and degradation of tight junction complexes.
RESULTS: Male Sprague-Dawley rats underwent coronary artery ligation to induce HF or sham surgery. Some HF rats received bilateral PVN microinjections of an interleukin 17 receptor A small interfering RNA or a scrambled small interfering RNA adeno-associated virus. Four weeks after coronary artery ligation, the permeability of the BBB was evaluated by intracarotid injection of fluorescent dyes (fluorescein isothiocyanate-dextran 10 kDa+rhodamine-dextran 70 kDa). Compared with sham-operated rats, HF rats exhibited an elevated extravasation of fluorescein isothiocyanate-dextran 10 kDa within the PVN but not in the brain cortex. The plasma interleukin 17A levels were positively correlated with fluorescein isothiocyanate 10 kDa extravasation in the PVN. The expression of caveolin-1, a transcytosis marker, was augmented, whereas the expression of tight junction proteins was diminished in HF rats. Interleukin 17 receptor A was identified within the endothelium of PVN microvessels. Treatment with interleukin 17 receptor A small interfering RNA led to a significant attenuation of fluorescein isothiocyanate 10 kDa extravasation in the PVN and reversed expression of caveolin-1 and tight junction-associated proteins in the PVN.
CONCLUSIONS: Collectively, these data indicate that BBB permeability within the PVN is enhanced in HF and is likely attributable to increased interleukin 17A/interleukin 17 receptor A signaling in the BBB endothelium, by promoting caveolar transcytosis and degradation of tight junction complexes.
摘要：
背景：外周炎性细胞因子的升高已被确定为心力衰竭（HF）中神经炎症和交感神经过度活动的积极贡献者。然而，这些细胞因子破坏血脑屏障（BBB）对大脑发挥作用的确切机制仍然难以捉摸。白细胞介素17A与各种神经系统疾病中的BBB破坏有关，在HF的循环和大脑中，其水平显着增加。本研究旨在确定BBB完整性是否在下丘脑室旁核（PVN）内受损，如果是这样,白细胞介素17A是否有助于心肌梗死诱导的HF中的BBB破坏。
结果：雄性Sprague-Dawley大鼠接受冠状动脉结扎以诱导HF或假手术。一些HF大鼠接受了白介素17受体A小干扰RNA或乱序小干扰RNA腺相关病毒的双侧PVN显微注射。冠状动脉结扎四周后，通过颈动脉内注射荧光染料(异硫氰酸荧光素-葡聚糖10kDa+罗丹明-葡聚糖70kDa)评估BBB的通透性.与假手术大鼠相比，HF大鼠在PVN中表现出异硫氰酸荧光素-葡聚糖10kDa的外渗，但在大脑皮层中没有。血浆白细胞介素17A水平与PVN中异硫氰酸荧光素10kDa外渗呈正相关。caveolin-1的表达，一种胞吞标记，被增强了，而HF大鼠中紧密连接蛋白的表达减少。在PVN微血管的内皮内鉴定出白介素17受体A。用白细胞介素17受体治疗一种小干扰RNA导致PVN中异硫氰酸荧光素10kDa外渗的显着减弱，并逆转PVN中caveolin-1和紧密连接相关蛋白的表达。
结论：总的来说，这些数据表明，在HF中，PVN内的BBB通透性增强，并且可能归因于BBB内皮中白介素17A/白介素17受体A信号传导的增加，通过促进空穴胞吞作用和紧密连接复合物的降解。
结果：雄性Sprague-Dawley大鼠接受冠状动脉结扎以诱导HF或假手术。一些HF大鼠接受了白介素17受体A小干扰RNA或乱序小干扰RNA腺相关病毒的双侧PVN显微注射。冠状动脉结扎四周后，通过颈动脉内注射荧光染料(异硫氰酸荧光素-葡聚糖10kDa+罗丹明-葡聚糖70kDa)评估BBB的通透性.与假手术大鼠相比，HF大鼠在PVN中表现出异硫氰酸荧光素-葡聚糖10kDa的外渗，但在大脑皮层中没有。血浆白细胞介素17A水平与PVN中异硫氰酸荧光素10kDa外渗呈正相关。caveolin-1的表达，一种胞吞标记，被增强了，而HF大鼠中紧密连接蛋白的表达减少。在PVN微血管的内皮内鉴定出白介素17受体A。用白细胞介素17受体治疗一种小干扰RNA导致PVN中异硫氰酸荧光素10kDa外渗的显着减弱，并逆转PVN中caveolin-1和紧密连接相关蛋白的表达。
结论：总的来说，这些数据表明，在HF中，PVN内的BBB通透性增强，并且可能归因于BBB内皮中白介素17A/白介素17受体A信号传导的增加，通过促进空穴胞吞作用和紧密连接复合物的降解。
