Involvement of the H1 Histamine Receptor, p38 MAP Kinase, Myosin Light Chains Kinase, and Rho/ROCK in Histamine-Induced Endothelial Barrier Dysfunction

Shaquria P Adderley, Xun E Zhang, Jerome W Breslin
Microcirculation: the Official Journal of the Microcirculatory Society, Inc 2015, 22 (4): 237-48

OBJECTIVE: The mechanisms by which histamine increases microvascular permeability remain poorly understood. We tested the hypothesis that H1 receptor activation disrupts the endothelial barrier and investigated potential downstream signals.

METHODS: We used confluent EC monolayers, assessing TER as an index of barrier function. HUVEC, HCMEC, and HDMEC were compared. Receptor expression was investigated using Western blotting, IF confocal microscopy and RT-PCR. Receptor function and downstream signaling pathways were tested using pharmacologic antagonists and inhibitors, respectively.

RESULTS: We identified H1-H4 receptors on all three EC types. H1 antagonists did not affect basal TER but prevented the histamine-induced decrease in TER. Blockade of H2 or H3 attenuated the histamine response only in HDMEC, while inhibition of H4 attenuated the response only in HUVEC. Combined inhibition of both PKC and PI3K caused exaggerated histamine-induced barrier dysfunction in HDMEC, whereas inhibition of p38 MAP kinase attenuated the histamine response in all three EC types. Inhibition of RhoA, ROCK, or MLCK also prevented the histamine-induced decrease in TER in HDMEC.

CONCLUSION: The data suggest that multiple signaling pathways contribute to histamine-induced endothelial barrier dysfunction via the H1 receptor.

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