Angiotensin‐(1‐7) Improves Integrated Cardiometabolic Function in Aged Mice

Abstract

BackgroundAging 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 models of cardiovascular and metabolic diseases 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 as well as decrease blood pressure and cardiac hypertrophy in healthy aged mice.MethodsSixteen month‐old male C57BL/6J mice received 6‐week Ang‐(1‐7) [400 ng/kg/min, n=9] or saline infusion (n=9) 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 and blood pressure was measured via a carotid artery catheter. Heart weight was measured at the end of experiments. Gene expression of tyrosine hydroxylase (index of sympathetic activity), inflammatory markers (IL10, IL1β, IL6, TNFα) and Ang II AT1 and Ang‐(1‐7) Mas receptors were measured in myocardial tissue by quantitative real‐time PCR and quantified with 2‐ΔΔCT methods.ResultsWe found that Ang‐(1‐7) 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=0.042]. The improvement in cardiac hypertrophy with Ang‐(1‐7) was associated with decreased tyrosine hydroxylase gene expression in the heart [Ang‐(1‐7): 0.4±0.1, saline: 0.9±0.1, p=0.014], with no effect on gene expression of inflammatory markers or angiotensin receptors (p>0.3). Ang‐(1‐7) did not alter body mass [Ang‐(1‐7): 46.5±2.0 g, saline: 45.9±1.5 g, p=0.792] or body composition (p>0.2). Ang‐(1‐7) also 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).ConclusionsChronic Ang‐(1‐7) treatment decreases blood pressure, cardiac hypertrophy, and markers of cardiac sympathetic activity as well as increases insulin sensitivity in aged mice. These beneficial cardiometabolic effects of Ang‐(1‐7) occurred in the absence of significant changes in body weight or composition. Overall, these data suggest that Ang‐(1‐7) may provide a novel pharmacological target to improve age‐related cardiovascular and metabolic risk.Support or Funding InformationNIH Pathway to Independence Award: R00 HL122507 to A.C. ArnoldAHA Postdoctoral Fellowship: 18POST33960087 to A.J. Miller