Journal
CELLS
Volume 10, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/cells10061489
Keywords
acidosis; hydrochloric acid; HCl; endothelial dysfunction; heat shock protein; HSP90 inhibition; AUY-922; acute lung injury
Categories
Funding
- CounterACT Program, National Institutes of Health Office of the Director (NIH OD)
- National Institute of Environmental Health Sciences (NIEHS) [UO1ES030674]
Ask authors/readers for more resources
Exposure to hydrochloric acid can impair pulmonary endothelial barrier function, but using HSP90 inhibitor AUY-922 can prevent and restore this damage. AUY-922 inhibits the molecular pathways activated by HCl, leading to cytoprotective effects.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available