Abstract
Angiotensin (Ang)-(1-7) is a beneficial renin–angiotensin system (RAS) hormone that elicits protective cardiometabolic effects in young animal models of hypertension, obesity, and metabolic syndrome. The impact of Ang-(1-7) on cardiovascular and metabolic outcomes during aging, however, remains unexplored. This study tested the hypothesis that Ang-(1-7) attenuates age-related elevations in blood pressure and insulin resistance in mice. Young adult (two-month-old) and aged (16-month-old) male C57BL/6J mice received Ang-(1-7) (400 ng/kg/min) or saline for six-weeks via a subcutaneous osmotic mini-pump. Arterial blood pressure and metabolic function indices (body composition, insulin sensitivity, and glucose tolerance) were measured at the end of treatment. Adipose and cardiac tissue masses and cardiac RAS, sympathetic and inflammatory marker gene expression were also measured. We found that chronic Ang-(1-7) treatment decreased systolic and mean blood pressure, with a similar trend for diastolic blood pressure. Ang-(1-7) also improved insulin sensitivity in aged mice to levels in young mice, without effects on glucose tolerance or body composition. The blood pressure–lowering effects of Ang-(1-7) in aged mice were associated with reduced sympathetic outflow to the heart. These findings suggest Ang-(1-7) may provide a novel pharmacological target to improve age-related cardiometabolic risk.
Highlights
Cardiovascular disease remains the leading cause of death in individuals greater than 65 years of age [1]
Aging is associated with weight gain and metabolic dysfunction, which exacerbates the progression of cardiovascular disease to increase morbidity and mortality [2]
Ang II is implicated in numerous cardiovascular diseases, with more recent evidence showing a role for elevated levels of this hormone in insulin resistance, obesity, and type 2 diabetes [5,6]
Summary
Cardiovascular disease remains the leading cause of death in individuals greater than 65 years of age [1]. Aging is associated with increased arterial stiffness, changes in cardiac structure and function, reduced parasympathetic tone, and elevated sympathetic outflow to the heart and other cardiovascular organs. Consistent with this, therapies blocking Ang II activity such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) effectively lower blood pressure, reduce risk for diabetes, prevent deficits in cardiovascular and metabolic functions and increase lifespan in aged animals and clinical populations [7,9,10,11]. ACE inhibitors and ARBs increase levels of the protective hormone Ang-(1-7), which our group and others have shown contributes to the beneficial cardiometabolic effects of these therapies in animal models of cardiovascular diseases, obesity, and diabetes [12,13,14,15]. Direct targeting of Ang-(1-7) may provide benefit beyond ACE inhibitors and ARBs by improving integrated cardiometabolic function while avoiding limiting side effects of these therapies
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