Abstract P118: Angiotensin-(1-7) Improves Cardiometabolic Function in Aged Mice

Abstract

Background: Aging is associated with impaired cardiometabolic function including insulin resistance, elevated blood pressure, and cardiac hypertrophy. Angiotensin (Ang)-(1-7) is a beneficial hormone of the renin-angiotensin system that improves control of blood pressure and glucose homeostasis in cardiovascular disease models in young mice. To our knowledge, no studies have evaluated the importance of Ang-(1-7) to integrated cardiometabolic function in aging. We hypothesized that Ang-(1-7) would improve insulin sensitivity and decrease blood pressure in healthy aged mice. Methods: Sixteen month-old male C57BL/6J mice received 6-week Ang-(1-7) [400 ng/kg/min, n=9] or saline (n=9) infusion via subcutaneous osmotic mini-pumps. All mice were fed standard chow diet (18% kcal from fat). During the last week of treatment, intraperitoneal insulin and glucose tolerance tests were performed. Body composition was measured by nuclear magnetic resonance imaging and blood pressure was measured via carotid artery catheter connected to a strain-gauge transducer and blood pressure analyzer. Heart weight and heart: body weight ratio was determined at the end of experiments. Results: Ang-(1-7) did not alter body mass [Ang-(1-7): 48.7±2.0 g, saline: 46.1±1.6 g, p =0.339] or body composition. Ang-(1-7) improved insulin sensitivity [Ang-(1-7): -2896±593 AUC, saline:-1171 ± 624 AUC , p =0.033] but did not affect fasting glucose levels [Ang-(1-7): 180±5 mg/dL, saline: 169±8 mg/dL, p =0.225] or glucose tolerance ( p =0.202). Ang-(1-7) also decreased systolic [Ang-(1-7): 105±2 mmHg, saline: 116±4 mmHg, P =0.031] diastolic [Ang-(1-7): 77±2 mmHg, saline: 83±2 mmHg, P =0.041], and mean [Ang-(1-7): 86±2 mmHg, saline: 94±3 mmHg, P = 0.023] blood pressure. Furthermore, Ang-(1-7) reduced heart weight [Ang-(1-7): 0.18±0.01 g; saline: 0.21±0.01 g, P =0.038] and heart to body weight ratio [Ang-(1-7): 0.004±0.001; saline: 0.005±0.001, P =0.049]. Conclusions: Chronic Ang-(1-7) treatment improves insulin sensitivity, lowers blood pressure, and attenuates cardiac hypertrophy in aged mice even in the absence of effects on body weight or composition. These data suggest Ang-(1-7) may provide a novel pharmacological target to improve age-related cardiometabolic disease.