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Protein complex formation with heat shock protein 90 in chronic hypoxia-induced pulmonary hypertension in newborn piglets

机译：慢性仔猪慢性缺氧性肺动脉高压中热激蛋白90与蛋白复合物的形成

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Aberrant interactions between heat shock protein (Hsp)90 and its client proteins could contribute to pulmonary hypertension. We tested the hypotheses that 1) the interaction between Hsp90 and its known client protein, endothelial nitric oxide synthase (eNOS), is impaired in pulmonary resistance arteries (PRAs) from piglets with pulmonary hypertension caused by exposure to 3 or 10 days of hypoxia and 2) Hsp90 interacts with the prostanoid pathway proteins prostacyclin synthase (PGIS) and/or thromboxane synthase (TXAS). We also determined whether Hsp90 antagonism with geldanamycin alters the agonist-induced synthesis of prostacyclin and thromboxane or alters PRA responses to these prostaglandin metabolites. Compared with normoxic piglets, less eNOS coimmunoprecipitated with Hsp90 in PRAs from hypoxic piglets. Despite reduced Hsp90-eNOS interactions, dilation to ACh was enhanced in geldanamycin-treated PRAs from hypoxic, but not normoxic, piglets. In PRAs from all groups of piglets, PGIS and TXAS coimmunoprecipitated with Hsp90. Geldanamycin reduced the ACh-induced synthesis of prostacyclin and thromboxane and altered responses to the thromboxane mimetic U-46619 in PRAs from all groups. Although geldanamycin enhanced responses to prostacyclin in PRAs from both groups of hypoxic piglets, geldanamycin had no effect on prostacyclin responses in PRAs from either group of normoxic piglets. Our findings indicate that Hsp90 influences both prostanoid and eNOS signaling in the pulmonary circulation of newborn piglets and that the impact of pharmacological inhibition of Hsp90 on these signaling pathways is altered during exposure to chronic hypoxia.
机译：热休克蛋白（Hsp）90及其客户蛋白之间的异常相互作用可能会导致肺动脉高压。我们测试了以下假设：1）Hsp90与已知的客户蛋白内皮型一氧化氮合酶（eNOS）之间的相互作用在暴露于缺氧3或10天的肺动脉高压仔猪的肺阻力动脉（PRA）中受损，并且2）Hsp90与类前列腺素途径蛋白前列环素合酶（PGIS）和/或血栓烷合酶（TXAS）相互作用。我们还确定了Hsp90与格尔德霉素的拮抗作用是否改变了激动剂诱导的前列环素和血栓烷的合成或改变了对这些前列腺素代谢物的PRA反应。与正常缺氧仔猪相比，低氧仔猪在PRA中与Hsp90共同免疫沉淀的eNOS较少。尽管降低了Hsp90-eNOS的相互作用，但是在低氧但非常氧的仔猪中，经格尔德霉素处理的PRA中ACh的扩增增强。在所有仔猪的PRA中，PGIS和TXAS与Hsp90共免疫沉淀。格尔德霉素减少了所有组中PRA中ACh诱导的ACh诱导的前列环素和血栓烷的合成，并改变了对血栓素模拟物U-46619的反应。尽管格尔德霉素增强了两组低氧仔猪对PRA的前列环素的反应，但格尔德霉素对两组正常氧仔猪对PRA的前列环素没有影响。我们的发现表明，Hsp90影响新生仔猪肺循环中的前列腺素和eNOS信号传导，并且在暴露于慢性低氧期间，Hsp90对这些信号传导途径的药理抑制作用会改变。

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