American Journal of Physiology: Lung Cellular and Molecular Physiology
Transendothelial hyperpermeability caused by numerous agonists is dependent on heat shock protein 90 (Hsp90) and leads to endothelial barrier dysfunction (EBD). Inhibition of Hsp90 protects and restores transendothelial permeability. Hyperacetylation of Hsp90, as by inhibitors of histone deacetylase (HDAC), suppresses its chaperone function and mimics the effects of Hsp90 inhibitors. In this study we assessed the role of HDAC in mediating lipopolysaccharide (LPS)-induced transendothelial hyperpermeability and acute lung injury (ALI). We demonstrate that HDAC inhibition protects against LPS-mediated EBD. Inhibition of multiple HDAC by the general inhibitors panobinostat or trichostatin provided protection against LPS-induced transendothelial hyperpermeability, acetylated and suppressed Hsp90 chaperone function, and attenuated RhoA activity and signaling crucial to endothelial barrier function. Treatment with the HDAC3-selective inhibitor RGFP-966 or the HDAC6-selective inhibitor tubastatin A provided partial protection against LPS-mediated transendothelial hyperpermeability. Similarly, knock down of HDAC3 and HDAC6 by specific small-interfering RNAs provided significant protection against LPS-induced EBD. Furthermore, combined pharmacological inhibition of both HDAC3 and -6 attenuated the inflammation, capillary permeability, and structural abnormalities associated with LPS-induced ALI in mice. Together these data indicate that HDAC mediate increased transendothelial hyperpermeability caused by LPS and that inhibition of HDAC protects against LPS-mediated EBD and ALI by suppressing Hsp90-dependent RhoA activity and signaling.
Original Publication Citation
Joshi, A. D., Barabutis, N., Birmpas, C., Dimitropoulou, C., Thangjam, G., Cherian-Shaw, M., . . . Catravas, J. D. (2015). Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function. American Journal of Physiology: Lung Cellular and Molecular Physiology, 309(12), L1410-L1419. doi:10.1152/ajplung.00180.2015
Joshi, Atul D.; Barabutis, Nektarios; Birmpas, Charalampos; Dimitropoulou, Christiana; Thangjam, Gagan; Cherian-Shaw, Mary; Dennison, John; and Catravas, John D., "Histone Deacetylase Inhibitors Prevent Pulmonary Endothelial Hyperpermeability and Acute Lung Injury By Regulating Heat Shock Protein 90 Function" (2015). Bioelectrics Publications. 200.