Interaction of Endothelial Cell Mineralocorticoid Receptor, Noncoding RNA, and Exosomes in Diet-Induced Vascular Stiffness and Insulin Resistance

Insulin-mediated capillary recruitment is important for increasing the vascular surface area for both insulin and glucose delivery and subsequent muscle glucose-uptake. Our recent data suggest Western diet (WD) induces vascular stiffness and impairs insulin-mediated capillary recruitment by activation of cell-specific endothelial cell (EC) mineralocorticoid receptor (MR). Here, we further hypothesized interaction of ECMR, noncoding RNA, and exosome contributes to WD-induced impairment of vascular stiffness and insulin sensitivity. Six week-old ECMR KO and littermate wild type control male mice were fed a mouse chow or WD containing excess fat (46%) and fructose (17.5%) for 16 weeks. Insulin sensitivity and vascular activity were determined by intraperitoneal glucose tolerance test and wire myograph system. ECMR KO mice prevented WD-impaired systemic insulin sensitivity and improved the aortic vasodilation responses to acetylcholine (10^-9-10^-4 mol/L) and insulin (0.1- 300 ng/ml), which were impaired by WD. The impairment of insulin sensitivity and vascular function was associated with abnormal expression of noncoding RNA including microRNA (miR)-7, -23, -34, -92, -429, -449, -466 as well as long noncoding RNA-kis2, -Mirt1, -Nron, -Cox2 examined by RNA sequencing, which are associated endothelium inflammation and vascular remodeling. In vitro cultured ECs, aldosterone (10^-7 mol) also increased EC exosome release and miR-103 expression. Furthermore, application of a miR103 inhibitor to ECs in vitro attenuated aldosterone-induced downregulation of serine (Ser) 1177/activation of endothelial nitric oxide synthase and upregulation of intercellular adhesion molecule 1. These findings suggest that increased ECMR signaling and associated abnormal expression and release of noncoding RNA and exosome play a key role in obesity-induced vascular stiffness and insulin resistance.