Pharmacological inhibition of HDAC6 attenuates endothelial barrier dysfunction induced by thrombin |
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| Authors: | Saito Shigeki Lasky Joseph A Guo Weichao Nguyen Hong Mai Antonello Danchuk Svitlana Sullivan Deborah E Shan Bin |
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| Institution: | aDepartment of Medicine, Tulane Medical School, New Orleans, LA, USA;bPasteur Institute-Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy;cDepartment of Microbiology, Tulane Medical School, New Orleans, LA, USA |
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| Abstract: | BackgroundEndothelial barrier dysfunction (EBD) involves microtubule disassembly and enhanced cell contractility. Histone deacetylase 6 (HDAC6) deacetylates α-tubulin, and thereby destabilizes microtubules. This study investigates a role for HDAC6 in EBD.MethodsEBD was induced with thrombin ± HDAC6 inhibitors (tubacin and MC1575), and assessed by transendothelial electrical resistance (TEER). Markers for microtubule disassembly (α-tubulin and acetylated α-tubulin) and contraction (phosphorylated myosin light chain 2, P-MLC2) were measured using immunoblots and immunofluorescence.Results and conclusionThrombin induced a ∼50% decrease in TEER that was abrogated by the HDAC6 inhibitors. Moreover, inhibition of HDAC6 diminished edema in the lung injured by lipopolysaccharide. Lastly, inhibition of HDAC6 attenuated thrombin-induced microtubule disassembly and P-MLC2. Our results suggest that HDAC6 can be targeted to limit EBD. |
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| Keywords: | HDAC6 Endothelial barrier Thrombin |
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