HDAC7 in MLCP‐mediated endothelial barrier preservation

Abstract

Acute lung injury (ALI) is an acute systemic inflammatory process characterized by pulmonary infiltrates hypoxemia and edema. ALI arises from a wide range of lung injuries such as toxins or inflammatory mediators. Despite the high level of mortality, to date no pharmacological therapies have been proven to improve ALI except from ventilation strategies. A deeper understanding of the pathogenic mechanisms involved remains a barrier to new and effective therapies that will reduce the vascular leak associated with ALI.A major cause of ALI is dysfunction of the pulmonary vascular endothelial barrier. Endothelial cells (EC) are a specialized cell type that line the lumen of the blood vessels serving every major organ system and provide a semi‐selective barrier between the blood and the interstitial space. Epigenetic mechanisms have emerged as a major regulator of enduring changes in cell behavior and the therapeutic potential of inhibiting histone deacetylases (HDACs) for the treatment of cardiovascular and inflammatory diseases is gaining increasing attention. In addition to histones, it has been shown that HDACs can deacetylate many non‐histone proteins to regulate cellular functions such as cytoskeletal acetylation and polymerization, and signal transduction. Further, it has been shown that HDAC inhibition is directly involved in EC barrier preservation, however, the molecular mechanisms of HDAC‐mediated EC barrier regulation remain largely unexplored.Our data indicate that the class IIa histone deacetylases comprising of HDACs 4, 5, 7, 9 are involved in the regulation of pulmonary vascular barrier in vitro and in lipopolysaccharide (LPS)‐induced murine model of ALI. These HDACs are known to function as transcriptional co‐repressors, however, they also are able to shuttle from nucleus to the cytoplasm thus becoming accessible for extra nuclear targets. We demonstrate that HDAC 7 is directly involved in LPS‐induced human lung microvascular EC (HLMVEC) barrier compromise. Further, barrier‐disruptive effects of LPS are accompanied by HDAC7 phosphorylation and its nuclear export. Conversely, agents that protect the EC barrier such as adenosine, decrease its phosphorylation. These data suggest the involvement of phosphatase activity in HDAC7‐mediated EC barrier regulation. Our results show that HDAC7 is a substrate for myosin light chain (MLC) phosphatase (MLCP) in HLMVEC. Conversely, down‐regulation of HDAC7 may affect MLCP activity. However, the physiological role of HDAC7/MLCP crosstalk in EC barrier regulation is currently unexplored. It is known that activation of MLCP leads to dephosphorylation of MLC thus opposing actomyosin contraction. Our newly published results suggest that MLCP activation may be involved in EC barrier preservation via the dephosphorylation of unconventional MLCP cytoskeletal targets such as moesin. Our results demonstrate a direct association between HDAC7 and moesin, suggesting a novel role of a HDAC7/MLCP/moesin signaling complex in the regulation of EC barrier. Collectively, these data demonstrate the involvement of HDAC7 activity in MLCP‐mediated EC barrier preservation and suggest, for the first time, the importance of HDAC7 nuclear export in pulmonary vascular injury induced by edemagenic agents such as LPS.Support or Funding InformationNIH; Contract grant number: HL101902This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.