Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice

Abstract

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 (<i>MasR^-/-</i> ) augments obesity-induced hypertension in males and abolishes protection of females. Male and female wild-type (<i>MasR^+/+</i> ) and <i>MasR^-/-</i> 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 <i>MasR^-/-</i> mice had reduced ejection fraction (EF) and fractional shortening than <i>MasR^+/+</i> mice. Male, but not female, HF-fed <i>MasR^+/+</i> 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 <i>MasR^-/-</i> mice had lower DBP than <i>MasR^+/+</i> mice. We quantified cardiac function after 1 mo of HF feeding in males of each genotype. HF-fed <i>MasR^-/-</i> mice had higher left ventricular (LV) wall thickness than <i>MasR^+/+</i> mice. Moreover, <i>MasR^+/+</i> , but not <i>MasR^-/-</i> , mice displayed reductions in EF from HF feeding that were reversed by ANG-(1-7) infusion. LV fibrosis was reduced in HF-fed <i>MasR^+/+</i> but not <i>MasR^-/-</i> 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 <i>MasR^+/+</i> but not <i>MasR^-/-</i> mice. MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.<b>NEW & NOTEWORTHY</b> 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-(1-7) 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.