The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction.
The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction.
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HSP90抑制剂AUY-922保护和修复人肺微血管内皮细胞免受盐酸诱导的内皮屏障功能障碍的影响。
DOI：
10.3390/cells10061489
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发表时间：
2021-06-13
期刊：
影响因子：
6
通讯作者：
Catravas JD
中科院分区：
文献类型：
--
作者：
Colunga Biancatelli RML;Solopov P;Gregory B;Catravas JD
暴露于盐酸（HCl）会急性导致哮喘样症状、急性呼吸窘迫综合征（ARDS），包括肺泡-毛细血管屏障受损和呼吸衰竭。为了更好地了解盐酸对肺内皮功能的直接影响，我们研究了盐酸诱导的人肺微血管内皮细胞（HLMVEC）原代培养的内皮屏障功能障碍的特点，定义了相关的分子途径，并测试了热休克蛋白90（HSP 90）抑制剂的潜在有益作用。HCl以时间和浓度依赖性方式损害屏障功能，并与蛋白激酶B（AKT）、Ras同系物家族成员A（RhoA）和肌球蛋白轻链2（MLC 2）的活化以及质膜VE-钙粘蛋白的丢失、皮质肌动蛋白的重排和内皮间间隙的出现相关。用第三代HSP 90抑制剂AUY-922预处理或后处理HLMVEC，可预防和恢复HCl诱导的内皮屏障功能障碍。AUY-922可增加HSP 70的表达，抑制细胞外信号调节激酶（ERK）和AKT的活化（磷酸化）。AUY-922还阻止HCl诱导的RhoA和MLC 2的活化以及质膜VE-钙粘蛋白的内化。我们的结论是，通过增加细胞保护蛋白的表达，干扰肌动球蛋白的收缩性，并提高连接蛋白的表达，抑制热休克蛋白90可能是一个有用的方法，盐酸诱导的内皮功能障碍和急性肺损伤的管理。
Exposure to hydrochloric acid (HCl) leads acutely to asthma-like symptoms, acute respiratory distress syndrome (ARDS), including compromised alveolo-capillary barrier, and respiratory failure. To better understand the direct effects of HCl on pulmonary endothelial function, we studied the characteristics of HCl-induced endothelial barrier dysfunction in primary cultures of human lung microvascular endothelial cells (HLMVEC), defined the involved molecular pathways, and tested the potentially beneficial effects of Heat Shock Protein 90 (HSP90) inhibitors. HCl impaired barrier function in a time- and concentration-dependent manner and was associated with activation of Protein Kinase B (AKT), Ras homolog family member A (RhoA) and myosin light chain 2 (MLC2), as well as loss of plasmalemmal VE-cadherin, rearrangement of cortical actin, and appearance of inter-endothelial gaps. Pre-treatment or post-treatment of HLMVEC with AUY-922, a third-generation HSP90 inhibitor, prevented and restored HCl-induced endothelial barrier dysfunction. AUY-922 increased the expression of HSP70 and inhibited the activation (phosphorylation) of extracellular-signal regulated kinase (ERK) and AKT. AUY-922 also prevented the HCl-induced activation of RhoA and MLC2 and the internalization of plasmalemmal VE-cadherin. We conclude that, by increasing the expression of cytoprotective proteins, interfering with actomyosin contractility, and enhancing the expression of junction proteins, inhibition of HSP90 may represent a useful approach for the management of HCl-induced endothelial dysfunction and acute lung injury.
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影响因子：
37.8
作者：
Iaccarino, G;Ciccarelli, M;Trimarco, B
通讯作者：
Trimarco, B
影响因子：
4
作者：
Catravas, John D.;Snead, Connie;Dimitropoulou, Christiana;Chang, Albert S. Y.;Lucas, Rudolf;Verin, Alexander D.;Black, Stephen M.
通讯作者：
Black, Stephen M.
DOI：
10.1165/rcmb.2007-0324oc
发表时间：
2008-11-01
影响因子：
6.4
作者：
Antonov, Alexander;Snead, Connie;Catravas, John D.
通讯作者：
Catravas, John D.
化学诱导的肺纤维化的鼠模型中的性别相关差异。
影响因子：
5.6
作者：
Solopov P;Colunga Biancatelli RML;Dimitropoulou C;Catravas JD
通讯作者：
Catravas JD
影响因子：
4.8
作者：
Karar J;Maity A
通讯作者：
Maity A