IL-33/ST2 receptor-dependent signaling in the development of pulmonary hypertension in Sugen/hypoxia mice.
IL-33/ST2 receptor-dependent signaling in the development of pulmonary hypertension in Sugen/hypoxia mice.
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DOI：
10.14814/phy2.15185
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发表时间：
2022-03
影响因子：
2.5
通讯作者：
Breen EC
中科院分区：
文献类型：
--
作者：
Indralingam CS;Gutierrez-Gonzalez AK;Johns SC;Tsui T;Cannon DT;Fuster MM;Bigby TD;Jennings PA;Breen EC
肺动脉高压（PAH）与显着的发病率和死亡率相关。 PAH 的特点是肺动脉重塑、右心室压力 (RVP) 升高，最终导致心力衰竭。肺内皮细胞可以通过警报素细胞因子感知机械损伤或病原体引起的危险或损伤。这些细胞因子可以发出增殖信号以恢复屏障完整性或异常的过度增殖和重塑。我们假设 IL-33 向肺动脉内皮细胞发出信号，使其在高血压条件下重塑反应和 RVP 升高期间增殖。为了检验这一假设，通过注射 10% O2 和 SU5416 (SUHX)，在 C57Bl/6J、IL-33 受体基因缺失 (ST2−/−) 和 MYD88 基因缺失 (MYD88−/−) 小鼠中诱导肺动脉高压 (PH)。评估了 RVP、动脉壁厚度、内皮细胞增殖以及 IL-33 水平和信号传导。回应 SUHX。 C57Bl/6J 小鼠对 SUHX 的反应增加了 RVP（49% 雄性和 70% 雌性；p < 0.0001），这种 SUHX 反应在 ST2−/− 小鼠中减弱（29% 雄性 p = 0.003；30% 雌性 p = 0.001），而在 MYD88−/− 小鼠中不存在。 SUHX C57Bl/6J 小鼠的壁厚度增加 (p = 0.005)，但 ST2−/− 或 MYD88−/− 小鼠的壁厚度没有增加。通过流式细胞术（CD31+/BrDU+；p = 0.02）和免疫荧光方法（Ki-67+）检测 C57Bl/6J 小鼠中的增殖细胞。 SUHX 增加了 IL-33 (p = 0.03)，但未观察到基因型效应 (p = 0.76)。我们观察到，在 hPAEC 中，IL-33 的表达受到 IL-33 和 DLL4 的调节。这些数据表明 IL-33/ST2 信号传导对于 PH 中的内皮细胞增殖反应至关重要。 IL-33/ST2 通路对于 Sugen/缺氧诱导的肺动脉高压的早期内皮细胞增殖反应至关重要，从而导致小阻力肺动脉的重塑。细胞内 Toll 样受体衔接蛋白 MYD88 与 IL-33/ST2 受体复合物协同调节右心室压力、右心室收缩力和重构。
Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. PAH is characterized by pulmonary artery remodeling, elevated right ventricular pressure (RVP) and, ultimately, cardiac failure. Pulmonary endothelial cells can sense danger or damage caused by mechanical injury or pathogens through alarmin cytokines. These cytokines can signal proliferation to restore barrier integrity or aberrant hyperproliferation and remodeling. We hypothesized that IL‐33 signals pulmonary artery endothelial cells to proliferate under hypertensive conditions during the remodeling response and rise in RVP. To test this hypothesis, pulmonary hypertension (PH) was induced in C57Bl/6J, IL‐33 receptor gene deleted (ST2−/−) and MYD88 gene deleted (MYD88−/−) mice by exposure to 10% O2 and SU5416 injections (SUHX). RVP, arterial wall thickness, endothelial cell proliferation and IL‐33 levels and signaling were evaluated. In response to SUHX. RVP increased in C57Bl/6J mice in response to SUHX (49% male and 70% female; p < 0.0001) and this SUHX response was attenuated in ST2−/− mice (29% male p = 0.003; 30% female p = 0.001) and absent in MYD88−/− mice. Wall thickness was increased in SUHX C57Bl/6J mice (p = 0.005), but not in ST2−/− or MYD88−/− mice. Proliferating cells were detected in C57Bl/6J mice by flow cytometry (CD31+/BrDU+; p = 0.02) and immunofluorescence methods (Ki‐67+). IL‐33 was increased by SUHX (p = 0.03) but a genotype effect was not observed (p = 0.76). We observed that in hPAECs, IL‐33 expression is regulated by both IL‐33 and DLL4. These data suggest IL‐33/ST2 signaling is essential for the endothelial cell proliferative response in PH. The IL‐33/ST2 pathway is essential for the early endothelial cell proliferative response in Sugen/hypoxia‐induced pulmonary hypertension that leads to remodeling of the small resistance pulmonary arteries. The intracellular toll‐like receptor adaptor protein, MYD88, synergizes with the IL‐33/ST2 receptor complex to regulate right ventricle pressure and right ventricle contractility and remodeling.
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DOI：
10.1073/pnas.0812690106
发表时间：
2009-06-02
影响因子：
11.1
作者：
Cayrol, Corinne;Girard, Jean-Philippe
通讯作者：
Girard, Jean-Philippe
影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
IL-33 通过上调血管内皮细胞中 HIF-1 α 和 VEGF 的表达来启动缺氧性肺动脉高压的血管重塑
影响因子：
11.1
作者：
Liu J;Wang W;Wang L;Chen S;Tian B;Huang K;Corrigan CJ;Ying S;Wang W;Wang C
通讯作者：
Wang C
影响因子：
20.1
作者：
Lai YC;Potoka KC;Champion HC;Mora AL;Gladwin MT
通讯作者：
Gladwin MT
DOI：
10.1073/pnas.1424236112
发表时间：
2015-06-09
影响因子：
11.1
作者：
Chen, Wei-Yu;Hong, Jaewoo;Lee, Richard T.
通讯作者：
Lee, Richard T.