C21 preserves endothelial function in the thoracic aorta from DIO mice: role for AT2, Mas and B2 receptors.

Compound 21 (C21), a selective agonist of angiotensin II type 2 receptor (AT2R), induces vasodilation through NO release. Since AT2R seems to be overexpressed in obesity, we hypothesize that C21 prevents the development of obesity-related vascular alterations. The main goal of the present study was to assess the effect of C21 on thoracic aorta endothelial function in a model of diet-induced obesity (DIO) and to elucidate the potential cross-talk among AT2R, Mas receptor (MasR) and/or bradykinin type 2 receptor (B2R) in this response. Five-week-old male C57BL6J mice were fed a standard (CHOW) or a high-fat diet (HF) for 6 weeks and treated daily with C21 (1 mg/kg p.o) or vehicle, generating four groups: CHOW-C, CHOW-C21, HF-C, HF-C21. Vascular reactivity experiments were performed in thoracic aorta rings. Human endothelial cells (HECs; EA.hy926) were used to elucidate the signaling pathways, both at receptor and intracellular levels. Arteries from HF mice exhibited increased contractions to Ang II than CHOW mice, effect that was prevented by C21. PD123177, A779 and HOE-140 (AT2R, Mas and B2R antagonists) significantly enhanced Ang II-induced contractions in CHOW but not in HF-C rings, suggesting a lack of functionality of those receptors in obesity. C21 prevented those alterations and favored the formation of AT2R/MasR and MasR/B2R heterodimers. HF mice also exhibited impaired relaxations to acetylcholine (ACh) due to a reduced NO availability. C21 preserved NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways. In conclusion, C21 favors the interaction among AT2R, MasR and B2R and prevents the development of obesity-induced endothelial dysfunction by stimulating NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways.

GC-MS based Gestational Diabetes Mellitus longitudinal study: Identification of 2-and 3-hydroxybutyrate as potential prognostic biomarkers.

Gestational Diabetes Mellitus (GDM) causes severe short- and long-term complications for the mother, fetus and neonate, including type 2-diabetes (T2DM) later in life. In this pilot study, GC-Q/MS analysis was applied for plasma metabolomics fingerprinting of 24 healthy and 24 women with GDM at different stages of gestation (second and third trimester) and postpartum (one and three months). Multivariate (unsupervised and supervised) statistical analysis was performed to investigate variance in the data, identify outliers and for unbiased assessment of data quality. Plasma fingerprints allowed for the discrimination of GDM pregnant women from controls both in the 2nd and 3rd trimesters of gestation. However, metabolic profiles tended to be similar after delivery. Follow up of these women revealed that 4 of them developed T2DM within 2 years postpartum. Multivariate PLS-DA models limited to women with GDM showed clear separation 3 months postpartum. In the 2nd trimester of gestation there was also a clear separation between GDM women that were normoglycemic after pregnancy and those with recognized postpartum T2DM. Metabolites that had the strongest discriminative power between these groups in the 2nd trimester of gestation were 2-hydroxybutyrate, 3-hydroxybutyrate, and stearic acid. We have described, that early GDM comprises metabotypes that are associated with the risk of future complications, including postpartum T2DM. In this pilot study, we provide evidence that 2-hydroxybutyrate and 3-hydroxybutyrate may be considered as future prognostic biomarkers to predict the onset of diabetic complications in women with gestational diabetes after delivery.