The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction
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 characteri...
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MDPI AG
2021-06-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/6/1489 |
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| author | Ruben M. L. Colunga Biancatelli Pavel Solopov Betsy Gregory John D. Catravas |
| author_facet | Ruben M. L. Colunga Biancatelli Pavel Solopov Betsy Gregory John D. Catravas |
| author_sort | Ruben M. L. Colunga Biancatelli |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T10:26:24Z |
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| id | doaj.art-7f1752450fa44646b90fcac76afbed93 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T10:26:24Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-7f1752450fa44646b90fcac76afbed932023-11-21T23:58:15ZengMDPI AGCells2073-44092021-06-01106148910.3390/cells10061489The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier DysfunctionRuben M. L. Colunga Biancatelli0Pavel Solopov1Betsy Gregory2John D. Catravas3Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USAFrank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USAFrank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USAFrank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USAExposure 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.https://www.mdpi.com/2073-4409/10/6/1489acidosishydrochloric acidHClendothelial dysfunctionheat shock proteinHSP90 inhibition |
| spellingShingle | Ruben M. L. Colunga Biancatelli Pavel Solopov Betsy Gregory John D. Catravas The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction Cells acidosis hydrochloric acid HCl endothelial dysfunction heat shock protein HSP90 inhibition |
| title | The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction |
| title_full | The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction |
| title_fullStr | The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction |
| title_full_unstemmed | The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction |
| title_short | The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction |
| title_sort | hsp90 inhibitor auy 922 protects and repairs human lung microvascular endothelial cells from hydrochloric acid induced endothelial barrier dysfunction |
| topic | acidosis hydrochloric acid HCl endothelial dysfunction heat shock protein HSP90 inhibition |
| url | https://www.mdpi.com/2073-4409/10/6/1489 |
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