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首页> 外文期刊>American Journal of Physiology >Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice
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Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

机译：没有炎症腺样ASC减少小鼠缺氧诱导的肺动脉高压

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Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxia-induced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-ip, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC~7~, and NLRP3~;~ mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC"7" mice was significantly lower than in WT exposed to hypoxia (40.8 ± 1.5 mmHg vs. 55.8 ± 2.4 mmHg, P < 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3~y~ mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-lp in WT and NLRP3~;~ mice, this response was absent in ASC-/~ mice. Moreover, ASCW~ mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension.
机译：肺动脉高压是一种严重的病症，可能导致过早死亡。涉及的机制是不完全理解的，尽管已经提出了免疫系统的作用。炎症是先天免疫系统的一部分，由效应性caspase-1和受体组成，其中核苷酸结合的寡聚化结构域样受体吡林结构域3（NLRP3）是最合适的和与适配器蛋白凋亡相关的相互作用含有Caspase-Recuitment结构域（ASC）的斑点蛋白质。为了探讨ASC和NLRP3炎症组分是否参与缺氧诱导的肺动脉高压，我们利用缺乏ASC和NLRP3的小鼠。在野生型（WT），ASC〜7〜和NLRP3〜;〜小鼠中，测量由炎症的活性Caspase-1，IL-18和IL-IP，测量肺匀浆，ASC〜7〜;〜小鼠和相关的表型变化缺氧暴露后表征肺动脉高压和右心室重塑。 ASC“7”小鼠的右心室收缩压（RVSP）显着低于暴露于缺氧的WT（40.8±1.5mmHg，55.8±2.4mmHg，P <0.001），表明缺乏ASC的小鼠的肺动脉高压显着降低。磁共振成像通过证明右心室重塑进一步支持这些结果。与WT缺氧相比，暴露于缺氧的NLRP3〜Y〜Y的RVSP不会显着改变。而缺氧增加了蛋白质水平的Caspase-1，IL-18和IL-LP在WT和NLRP3〜;〜小鼠中，在ASC-/〜小鼠中不存在这种反应。此外，ASCW〜小鼠在动脉周围显示出降低的肌肉化和胶原沉积。总之，缺氧诱导的右心室压力和重塑在缺乏炎症组合蛋白ASC的小鼠中衰减，表明炎症在肺动脉高压的发病机制中发挥着重要作用。

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