Abstract P114: Mas Receptor Deficiency Increases Diastolic Blood Pressure and Reduces Cardiac Function in Obese Female Mice

Abstract

Objective: We recently demonstrated that protection of female mice from obesity-induced hypertension was associated with increased plasma concentrations of angiotensin-(1-7) (Ang-(1-7)). Ang-(1-7) is a ligand for Mas receptors (MasR), where the peptide has been reported to promote endothelial release of nitric oxide and reduce blood pressure. In this study, we hypothesized that MasR deficiency will abolish protection of female high fat (HF)-fed mice from the development of obesity-induced hypertension. Methods and Results: Female (8 weeks, C57BL/6) wild type (MasR+/+) and whole body MasR deficient mice (MasR-/-) were fed a HF diet (60% Kcal as fat) for 16 weeks. MasR deficiency had no effect on the development of obesity or glucose intolerance in HF-fed female mice. At week 16 of HF feeding, blood pressure was quantified by radiotelemetry. Deficiency of MasR resulted in a significant decrease in pulse pressures of HF-fed females (24hr average: MasR+/+, 37.7 ± 1.5 mmHg; MasR-/-, 33.1 ± 1.0 mmHg; P<0.05). Diastolic blood pressures (DBP) of HF-fed female MasR-/- mice were modestly elevated during the night cycle compared to controls (DBP night: MasR+/+, 91.5 ± 2.0 mmHg; MasR-/-, 96.6 ± 1.3 mmHg; P=0.06). However, systolic blood pressure, mean arterial pressure and heart rate were not significantly different between genotypes. Assessment of left ventricular function by ultrasound demonstrated significant reductions in stroke volume (MasR+/+, 44.3 ± 1.6 μl; MasR-/-, 36.3 ± 2.1 μl), ejection fraction (MasR+/+, 57.1 ± 1.2; MasR-/-, 50.1 ± 2.7%) and fractional shortening (MasR+/+, 29.7 ± 0.8; MasR-/-, 25.3 ± 1.7%) in HF-fed MasR-/- females compared to controls. Conclusion: These results demonstrate that MasR deficiency promotes elevated diastolic blood pressures and reduced cardiac function in obese female mice, suggesting that the Ang-(1-7)/MasR axis protects females from obesity-hypertension. Moreover, these results suggest that MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.