title: 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 (MasR-/-) augments obesity-induced hypertension in males and abolishes protection of females. Male and female wild-type (MasR+/+) andMasR-/-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 femaleMasR-/-mice had reduced ejection fraction (EF) and fractional shortening thanMasR+/+mice. Male, but not female, HF-fedMasR+/+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-fedMasR-/-mice had lower DBP thanMasR+/+mice. We quantified cardiac function after 1 mo of HF feeding in males of each genotype. HF-fedMasR-/-mice had higher left ventricular (LV) wall thickness thanMasR+/+mice. Moreover,MasR+/+, but notMasR-/-, mice displayed reductions in EF from HF feeding that were reversed by ANG-(1-7) infusion. LV fibrosis was reduced in HF-fedMasR+/+but notMasR-/-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) inMasR+/+but notMasR-/-mice. MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.NEW & NOTEWORTHYMasR 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.
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
authors.forename: Robin
authors.initials: R
authors.lastname: Shoemaker
authors.affiliation: Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky; and.
authors.forename: David
authors.initials: D
authors.lastname: Powell
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky.
authors.forename: Wen
authors.initials: W
authors.lastname: Su
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
authors.forename: Sean
authors.initials: S
authors.lastname: Thatcher
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky; lcassis@uky.edu.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cassis
mesh_terms: D000803:Angiotensin I / Q000097:blood / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D059305:Diet, High-Fat / Q000009:adverse effects; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006334:Heart Function Tests; D006973:Hypertension / Q000209:etiology / Q000235:genetics; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; C118790:angiotensin I (1-7)
keywords: angiotensin-(1–7); hypertension; obesity