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. 2024 Oct;1870(7):167335.
doi: 10.1016/j.bbadis.2024.167335. Epub 2024 Jul 3.

Ethanol promotes protease activated receptor 1: Chemokine (C-X-C motif) receptor 4 heteromerization and enhances thrombin-induced impairment of human lung endothelial cell barrier function

Michelle Y McGee  1 , Garrett A Enten  1 , Sadia N Boshra  2 , Ololade Ogunsina  1 , Vadim Gaponenko  3 , Xianlong Gao  1 , Matthias Majetschak  4
Affiliations

Ethanol promotes protease activated receptor 1: Chemokine (C-X-C motif) receptor 4 heteromerization and enhances thrombin-induced impairment of human lung endothelial cell barrier function

Michelle Y McGee et al. Biochim Biophys Acta Mol Basis Dis. 2024 Oct.

Abstract

  1. Ethanol enhances the propensity of PAR1 and CXCR4 to form heteromers.

  2. Ethanol increases PAR1:CXCR4 heteromer expression in human lung microvascular endothelial cells (HULEC-5a).

  3. Ethanol enhances the efficacy of PAR1 to activate Gα12 upon thrombin stimulation in cells co-expressing CXCR4.

  4. Ethanol dose-dependently increases the efficacy of thrombin to impair HULEC-5a barrier function at clinically relevant concentrations.

  5. Interference with PAR1:CXCR4 heteromerization mitigates effects of ethanol on thrombin-induced impairment of HULEC-5a barrier function.

  6. Our findings provide a molecular mechanism that is likely to contribute to the increased risk of acute respiratory distress syndrome with alcohol abuse.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthias Majetschak reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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