Glucagon-like peptide-1 improves vascular endothelial dysfunction in hypertensive mice via CREB-driven...

Agents targeting the glucagon-like peptide-1 (GLP-1) signalling pathway, including dipeptidyl peptidase 4 (DPP-4) inhibitors and GLP-1 receptor agonists, exert biological effects through regulating long noncoding RNAs (lncRNAs). We previously identified ENSMUST00000155383 (lncRNA 155383) as a potential contributor to DPP-4 inhibitor MK-626-induced endothelial nitric oxide synthase (eNOS) phosphorylation in endothelial cells from hypertensive mice. However, the regulatory mechanism of GLP-1 on lncRNA 155383 and role of this lncRNA in endothelial homeostasis remain unclear.

Mice were treated with shRNA adenovirus for lncRNA 155383 knockdown. Vascular function was evaluated by wire myograph. Molecular mechanisms were investigated using ChIP-qPCR, subcellular fractionation analysis, fluorescence in situ hybridization and dual-luciferase reporter assays.

LncRNA 155383 knockdown abolished the vaso-protective effects of MK-626 in hypertensive mice and induced endothelial dysfunction in normotensive controls. MK-626 activated cAMP-response element-binding protein (CREB), which bound to the lncRNA 155383's promoter, thereby driving its transcription. LncRNA 155383 was mainly localized in the cytoplasm, where it functioned as a competing endogenous RNA, sponging miR-214-3p to preserve plasma membrane Ca²⁺ ATPase 4 (PMCA4) expression. Up-regulated PMCA4 subsequently activated the Akt/eNOS pathway, restoring endothelial function. Similar ameliorative effect of a GLP-1 receptor agonist exendin-4 on angiotensin II-induced endothelial injury in vitro was observed.

GLP-1 might improve endothelial function via CREB-driven lncRNA 155383 transcription, which sponges miR-214-3p to up-regulate PMCA4 and activate downstream Akt/eNOS signalling. These findings uncover a novel molecular basis of GLP-1-mediated vascular protection and implicate lncRNA 155383 as a possible therapeutic target in hypertension.