The disruption of the lung vascular endothelial cell (EC) barrier, leading to pulmonary edema, is a key characteristic of acute lung injury (ALI). Despite the severity of ALI, there are no effective treatments available to date. Our research has shown that class IIa histone deacetylase, HDAC7, but not its closely related homologs HDAC4 and HDAC5, is upregulated in human lung microvascular ECs (HLMVECs) in response to the edemagenic agent lipopolysaccharide (LPS). Deleting HDAC7 specifically in ECs reduces LPS-induced ALI in mice and mitigates HLMVEC barrier disruption, indicating a pro-edemagenic role for EC HDAC7 in ALI. The increase in EC permeability induced by LPS is associated with HDAC7 phosphorylation and its export from the nucleus, suggesting that extranuclear HDAC7 activity plays a role in the LPS response. Phosphorylated HDAC7 remains in the cytoplasm, where it may interact with extranuclear targets. We found that HDAC7 interacts with Ser/Thr phosphatase 2A (PP2A), which can dephosphorylate HDAC7 and is essential for functional EC junctions (ECJs). Additionally, HDAC7 interacts with PP2A substrates, the junctional proteins desmoplakin (DSP) and plakoglobin (PLN), implicating HDAC7 in the regulation of ECJs. Interestingly, LPS specifically upregulates DSP, which is accompanied by DSP phosphorylation and inhibition, while PP2A dephosphorylates and reactivates it. Our data suggest that PP2A is activated by hepatocyte growth factor (HGF), which may exert its protective effects on the EC barrier through GAB1/SHP2-mediated signaling. Although the connections between HGF-mediated PP2A activation, GAB1/SHP2 signaling, and HDAC7-mediated EC barrier dysfunction are not fully established, we observed that the phosphorylation status of HDAC7 and its interactions with PP2A and ECJ partners modulate intracellular signaling to regulate the EC barrier.
Patil et al. (Fri,) studied this question.
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