Sitagliptin via the activation of AMPK/eNOS signaling improves vascular endothelial function by suppressing Creb5/lncRNA ENSMUST00000213271 axis in obese mice

Abstract Purpose This study aimed to investigate whether sitagliptin, a dipeptidyl peptidase-4 inhibitor, improved endothelial function by modulating lncRNAs in obese mice and clarify the underlying molecular mechanism. Methods Male C57BL/6J mice were fed with high-fat diet for four months to induce obesity and some obese mice were treated with sitagliptin for the last one month. Levels of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucagon-like peptide-1 (GLP-1) in plasma were detected by ELISA. LncRNA expression profile was analyzed via microarray. Aortic relaxations were examined by myograph. Protein expressions and phosphorylations were determined by Western blot. The differentially expressed lncRNAs were validated by qRT-PCR. Results Levels of TC and LDL were increased, concentrations of HDL and GLP-1 were decreased, and aortic endothelium-dependent relaxations were impaired in obese mice; sitagliptin reversed all above effects. Moreover, the altered expression profile of lncRNAs in the obese mouse aortae could be modulated by sitagliptin. qRT-PCR showed that lncRNA ENSMUST00000213271 was up-regulated in obese mouse aortae and endothelial cells but could be down-regulated by sitagliptin, which was consistent with microarray analysis. Importantly, we first revealed the regulatory effect of Creb5 on lncRNA ENSMUST00000213271. Furthermore, knockdown of either Creb5 or lncRNA ENSMUST00000213271 restored the activation of AMPK/eNOS in obese mouse aortic endothelial cells. Conclusion: Our results elucidate that sitagliptin ameliorated endothelial dysfunction by suppressing Creb5/lncRNA ENSMUST00000213271 and subsequently restoring AMPK/eNOS activation in obese mice. This study will provide the new evidence for the benefits of GLP-1 against vasculopathy in obesity.