Inflammation-induced GLP-1R promoter hypermethylation limits GLP-1RA efficacy in acute lung injury, with GLP-1R restoration improving outcomes.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent critical conditions with high mortality and limited therapeutic options. While GLP-1 receptor agonists (GLP-1RAs) possess potent anti-inflammatory properties, their efficacy in ALI has been controversial, suggesting an underlying mechanism limiting their protective effects. Understanding this therapeutic resistance is crucial for developing more effective treatments for severe lung inflammation. This research investigates the molecular basis for the heterogeneous response to GLP-1RAs in ALI.

Researchers established an ALI mouse model and utilized three cell lines: vascular endothelial cells, human bronchial epithelial cells, and mouse alveolar epithelial cells. Inflammation was induced via lipopolysaccharide (LPS) stimulation. They characterized GLP-1R expression and investigated epigenetic modifications using assay for transposase-accessible chromatin sequencing, targeted bisulfite sequencing, and western blotting. Interventions included GLP-1RA treatment, lentivirus-mediated GLP1R overexpression in cells, and adeno-associated virus-mediated Glp1r restoration in mice, compared against GLP-1RA monotherapy.

In vivo, the study revealed significant transcriptional repression of GLP-1R in the lung tissues of ALI mice. Consistently, lipopolysaccharide (LPS) stimulation markedly reduced GLP-1R expression across all three tested cell lines. Mechanistically, integrated analyses demonstrated that LPS upregulated DNA methyltransferase 3A/3B expression. This upregulation induced hypermethylation of the GLP-1R promoter, which in turn reduced chromatin accessibility and ultimately triggered GLP-1R transcriptional silencing. This inflammation-mediated epigenetic blockade was identified as a key contributor to therapeutic resistance of vascular endothelial cells to the anti-inflammatory effects of GLP-1RAs. > Lentivirus-mediated GLP1R overexpression in vascular endothelial cells effectively restored the anti-inflammatory capacity of GLP-1RAs and ameliorated cellular energy metabolism disorders. Furthermore, in vivo experiments validated that adeno-associated virus-mediated Glp1r restoration in the lungs of ALI mice exerted superior protective effects compared with GLP-1RA monotherapy.