Integrative Cardiovascular Physiology and Pathophysiology: Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice

摘要

Wang Y, Shoemaker R, Powell D, Su W, Thatcher S, Cassis L. Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice. Am J Physiol Heart Circ Physiol 312: H459-H468, 2017. First published December 16, 2016; doi:10.1152/ajpheart.00498.2016.—Angiotensin-(1-7) [ANG-(1-7)] acts at Mas receptors (MasR) to oppose effects of angiotensin II (ANG II). Previous studies demonstrated that protection of female mice from obesity-induced hypertension was associated with increased systemic ANG-(1-7), whereas male obese hypertensive mice exhibited increased systemic ANG II. We hypothesized that MasR deficiency (MasR"'") augments obesity-induced hypertension in males and abolishes protection of females. Male and female wild-type (MasR~+/+) and MasR~-/- mice were fed a low-fat (LF) or high-fat (HF) diet for 16 wk. MasR deficiency had no effect on obesity. At baseline, male and female MasR~-/- mice had reduced ejection fraction (EF) and fractional shortening than MasR~+/+ mice. Male, but not female, HF-fed MasR~+/+ mice had increased systolic and diastolic (DBP) blood pressures compared with LF-fed controls. In HF-fed females, MasR deficiency increased DBP compared with LF-fed controls. In contrast, male HF-fed MasR~-/- mice had lower DBP than MasR~+/+ mice. We quantified cardiac function after 1 mo of HF feeding in males of each genotype. HF-fed MasR~+/+ mice had higher left ventricular (LV) wall thickness than MasR~+/+ mice. Moreover, MasR~+/+, but not MasR~-/-, mice displayed reductions in EF from HF feeding that were reversed by ANG-(1-7) infusion. LV fibrosis was reduced in HF-fed MasR~+/+ but not MasR~-/- ANG-(1-7)-infused mice. These results demonstrate that MasR deficiency promotes obesity-induced hypertension in females. In males, HF feeding reduced cardiac function, which was restored by ANG-(1-7) in MasR~+/+ but not MasR~-/- mice. MasR agonists may be effective therapies for obesity-associated cardiovascular conditions. NEW & NOTEWORTHY MasR deficiency abolishes protection of female mice from obesity-induced hypertension. Male MasR-deficient obese mice have reduced blood pressure and declines in cardiac function. ANG-(l-7) infusion restores obesity-induced cardiac dysfunction of wild-type, but not MasR-deficient, male mice. MasR agonists may be cardioprotective in obese males and females.