Date Available

3-23-2016

Year of Publication

2016

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

Advisor

Dr. Lisa A. Cassis

Abstract

Obesity is strongly associated with hypertension and cardiovascular diseases. An activated renin-angiotensin system (RAS) has long been suggested as a critical contributor to elevated blood pressure with obesity. Angiotensin II (AngII), the main effector of an activated RAS, can be catabolized by angiotensin-converting enzyme 2 (ACE2) to form angiotensin-(1-7) (Ang-(1-7)), which, acting through the mas receptor (MasR), has been shown to oppose the effects of an activated RAS. Therefore, further understanding of the mechanisms of this counter-regulatory arm, called the ACE2/Ang-(1-7)/MasR axis, may lead to new therapies for obesity-induced hypertension. Previously, we demonstrated that differences in the regulation of ACE2 in a tissue-specific manner contribute to sexual dimorphism of diet-induced obesity-hypertension in mice. Whereas male mice fed a high fat (HF) diet developed hypertension, HF-fed female mice were protected from obesity-hypertension, and this was associated with increased activity of ACE2 in adipose tissue of females. Both upregulation of adipose ACE2 and protection against obesity-hypertension were lost when females were ovariectomized (OVX). We hypothesized that estrogen-mediated increases in adipose ACE2 reduce the AngII/Ang-(1-7) peptide balance and protect females from obesity-hypertension. To test this hypothesis, we first determined if estrogen restores protection of Ovx female mice from obesity-hypertension, and therapeutically protects male mice from obesity-hypertension. We demonstrated that estrogen administration to Ovx HF-fed females activates adipose ACE2, reduces plasma Ang II concentrations, and decreases blood pressure in wildtype, but not of ACE2-deficient obese females. In contrast, estrogen administration to HF-fed male mice had no on the development of obesity-hypertension, regardless of genotype. These results demonstrate that estrogen protects female mice from obesity-hypertension through an ACE2-dependent mechanism. Next we defined the role of MasR deficiency on the development of obesity-hypertension in male and female mice. In HF-fed MasR-deficient female mice, diastolic blood pressure (DBP) was significantly elevated compared to LF-fed controls, suggesting that protection from obesity-hypertension was abolished by MasR deficiency. In contrast, HF-fed male mice with MasR deficiency exhibited reduced blood pressure compared to wildtype controls which was associated with reduced cardiac function. Overall, these studies indicate that the ACE2/Ang-(1-7)/MasR axis plays an important role in sexual dimorphism of obesity-hypertension, and in the regulation of cardiac function. Moreover, these studies suggest that the effects of this counter-regulatory arm of the RAS may be sex-specific.

Digital Object Identifier (DOI)

http://dx.doi.org/10.13023/ETD.2016.037

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