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Role of IL-33 receptor (ST2) deletion in diaphragm contractile and mitochondrial function in the Sugen5416/hypoxia model of pulmonary hypertension
Respiratory Physiology & Neurobiology ( IF 2.3 ) Pub Date : 2021-09-08 , DOI: 10.1016/j.resp.2021.103783
Daniel T Cannon 1 , Leonardo Nogueira 2 , Alma K Gutierrez-Gonzalez 3 , Natalie K Gilmore 3 , Timothy D Bigby 3 , Ellen C Breen 3
Affiliation  

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right ventricular failure. Skeletal muscle maladaptations limit physical activity and may contribute to disease progression. The role of alarmin/inflammatory signaling in PAH respiratory muscle dysfunction is unknown. We hypothesized that diaphragm mitochondrial and contractile functions are impaired in SU5416/hypoxia-induced pulmonary hypertension due to increased systemic IL-33 signaling. We induced pulmonary hypertension in adult C57Bl/6 J (WT) and ST2 (IL1RL1) gene ablated mice by SU5416/hypoxia (SuHx). We measured diaphragm fiber mitochondrial respiration, inflammatory markers, and contractile function ex vivo. SuHx reduced coupled and uncoupled permeabilized myofiber respiration by ∼40 %. During coupled respiration with complex I substrates, ST2−/− attenuated SuHx inhibition of mitochondrial respiration (genotype × treatment interaction F[1,67] = 3.3, p = 0.07, η2 = 0.04). Flux control ratio and coupling efficiency were not affected by SuHx or genotype. A higher substrate control ratio for succinate was observed in SuHx fibers and attenuated in ST2-/- fibers (F[1,67] = 5.3, p < 0.05, η2 = 0.07). Diaphragm TNFα, but not IL-33 or NFkB, was increased in SuHx vs. DMSO in both genotypes (F[1,43] = 4.7, p < 0.05, η2 = 0.1). Diaphragm force-frequency relationships were right-shifted in SuHx vs. WT (F[3,440] = 8.4, p < 0.05, η2 = 0.0025). There was no effect of ST2−/− on the force-frequency relationship. Force decay during a fatigue protocol at 100 Hz, but not at 40 Hz, was attenuated by SuHx vs. DMSO in both genotypes (F[1,41] = 5.6, p < 0.05, η2 = 0.11). SuHx mice exhibit a modest compensation in diaphragm contractility and mitochondrial dysfunction during coupled respiration; the latter partially regulated through ST2 signaling.



中文翻译:

IL-33 受体 (ST2) 缺失在 Sugen5416/肺动脉高压缺氧模型中膈肌收缩和线粒体功能中的作用

肺动脉高压 (PAH) 是肺血管系统的一种进行性疾病,可导致右心室衰竭。骨骼肌适应不良会限制身体活动并可能导致疾病进展。警报素/炎症信号在 PAH 呼吸肌功能障碍中的作用尚不清楚。我们假设由于全身性 IL-33 信号传导增加,SU5416/缺氧诱导的肺动脉高压中隔膜线粒体和收缩功能受损。我们通过 SU5416/缺氧 (SuHx) 在成年 C57Bl/6 J (WT) 和 ST2 (IL1RL1) 基因消融小鼠中诱导肺动脉高压。我们测量了隔膜纤维线粒体呼吸、炎症标志物和离体收缩功能. SuHx 将耦合和非耦合的透化肌纤维呼吸降低了 ~40%。在与复合物 I 底物耦合呼吸期间,ST2 -/-减弱了 SuHx 对线粒体呼吸的抑制(基因型 × 治疗相互作用 F[1,67] = 3.3,p = 0.07,η 2  = 0.04)。通量控制比和耦合效率不受 SuHx 或基因型的影响。在 SuHx 纤维中观察到较高的琥珀酸盐底物控制比,在 ST2 -/-纤维中减弱 (F[1,67] = 5.3, p < 0.05, η 2  = 0.07)。在两种基因型中,SuHx 与 DMSO 相比,隔膜 TNFα 增加,但 IL-33 或 NFkB 没有增加(F[1,43] = 4.7,p < 0.05,η 2 = 0.1)。SuHx 与 WT 中的隔膜力-频率关系右移(F[3,440] = 8.4,p < 0.05,η 2  = 0.0025)。ST2 -/-对力-频率关系没有影响。SuHx 与 DMSO 在两种基因型中的 100 Hz(但不是 40 Hz)疲劳协议期间的力衰减(F[1,41] = 5.6,p < 0.05,η 2  = 0.11)。SuHx 小鼠在耦合呼吸过程中对膈肌收缩和线粒体功能障碍表现出适度的补偿;后者通过 ST2 信号进行部分调节。

更新日期:2021-09-13
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