GLP-1 improves vascular dysfunction in hypertensive mice via CREB-driven lncRNA 155383 transcription

Cardiovascular disease, particularly hypertension, is a leading cause of morbidity and mortality, often characterized by endothelial dysfunction. While glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors are known to exert cardiovascular benefits beyond glycemic control, the precise molecular mechanisms, especially involving long non-coding RNAs (lncRNAs), remain underexplored. Previous work hinted at lncRNA 155383's role in DPP-4 inhibitor-induced eNOS phosphorylation in hypertensive endothelial cells, but its full regulatory pathway and contribution to endothelial homeostasis were unclear, representing a critical gap in understanding GLP-1's pleiotropic effects.

Researchers investigated the role of lncRNA 155383 in vascular function using both in vivo and in vitro models. Mice were subjected to shRNA adenovirus for lncRNA 155383 knockdown to assess its impact on vaso-protective effects of the DPP-4 inhibitor MK-626. Vascular function was meticulously evaluated using wire myograph assays. Molecular mechanisms were elucidated through a battery of techniques including ChIP-qPCR to identify protein-DNA interactions, subcellular fractionation analysis to determine lncRNA localization, fluorescence in situ hybridization (FISH), and dual-luciferase reporter assays to confirm transcriptional regulation and RNA-RNA interactions. An in vitro model of angiotensin II-induced endothelial injury was also used to test the GLP-1 receptor agonist exendin-4.

Knockdown of lncRNA 155383 completely abolished the vaso-protective effects of MK-626 in hypertensive mice, and remarkably, induced endothelial dysfunction even in normotensive control animals. Mechanistically, MK-626 was found to activate cAMP-response element-binding protein (CREB), which subsequently bound to the promoter region of lncRNA 155383, thereby driving its transcription. Subcellular analysis revealed that lncRNA 155383 was predominantly localized in the cytoplasm. Here, it acted as a competing endogenous RNA (ceRNA), effectively sponging miR-214-3p to preserve the expression of plasma membrane Ca2+ ATPase 4 (PMCA4).

Up-regulated PMCA4 subsequently activated the Akt/eNOS pathway, a critical cascade for nitric oxide production, ultimately restoring endothelial function. A similar ameliorative effect of the GLP-1 receptor agonist exendin-4 was observed on angiotensin II-induced endothelial injury in vitro, reinforcing the pathway's relevance to GLP-1 signaling.