Abstract 890: Vascular MicroRNA-204 Promotes Diabetes-Associated Endothelial Dysfunction

Background: The failure to achieve a decline in blood pressure at rest in type 2 diabetes (T2D) patients is believed to reflect endothelial dysfunction, and it increases the risk of coronary artery disease. Previously we discovered that the intestinal microbes govern vascular endothelial function through microRNA-204 (miR-204). The objective of this study was to investigate whether miR-204 contributes to diabetes-associated vascular endothelial dysfunction. Methods: To test miR-204's role in diabetes we generated leptin receptor mutant genetically diabetic mice lacking miR-204 (db/db-miR-204 -/- ). The vascular function was assessed by determining the vessel relaxation of phenylephrine-induced precontracted aortic rings. To ascertain the vascular miR-204 role in endothelial function ex-vivo experiments were performed, on aorta isolated from db/db mice, using miR-204 inhibitor. The miR-204 expression and localization were done using quantitative real-time PCR (qRT-PCR) and In-situ hybridization (ISH) assays. Results: A significant increase in the vascular miR-204 expression was observed in the thoracic aorta of db/db mice compared to the age-matched control (208.80 ± 45.60 vs. 80.65 ± 13.11; p<0.05). The genetic deletion of miR-204 rescues endothelial function (improved vascular relaxation; 36.17 ± 7.42 vs. 76.56 ± 4.43; p<0.001). The db/db-miR-204 -/- mice develop obesity but are protected against diabetes (as evidenced by better glycemic control). Ex-vivo inhibition of miR-204 rescues diabetes-associated impairment of endothelium-dependent vasorelaxation (18.10 ± 2.16 vs. 50.64 ± 7.66; p<0.01). Next, we plan to identify the molecular mediator of miR-204 effects on the vascular endothelial function using Argonaute 2-crosslinked immunoprecipitation (Ago2-CLIP) assay. Conclusions: Type 2 diabetes upregulates vascular miR-204, and genetic deletion of miR-204 rescues diabetes-associated impairment in endothelial function.