Grants and Contracts Details
Obesity has been demonstrated to be the primary factor contributing to a rising prevalence of hypertension in the United States. In general, women are thought to be protected from developing hypertension before menopause, but after menopause the prevalence of hypertension in females exceeds that of males. Results from our laboratory suggest that an activated adipocyte renin-angiotensin system (RAS) may be a link between obesity and hypertension. We have recently demonstrated that adipose tissue can serve as a predominant source of systemic angiotensin II (AngII) in obese male mice. We also demonstrated that adipocytes express angiotensin converting enzyme 2 (ACE2), which cleaves AngII to form the vasodilator peptide, angiotensin-(1-7) (Ang-(1-7)). In male obese hypertensive mice exhibiting increased adipose-derived systemic AngII, adipose ACE2 expression was reduced and systemic Ang-(1-7) concentrations plummeted to levels of an ACE2 knockout. These results suggest that reductions in ACE2 in an expanded adipose mass make AngII the predominant adipose-derived RAS peptide, contributing to hypertension in obese male mice. In contrast, obese female mice were totally resistant to the development of hypertension despite greater adiposity. Remarkably, female normotensive obese mice exhibited increased adipose ACE2 activity associated with elevated plasma Ang-(1-7) concentrations. Deficiency of ACE2 converted obese females to a hypertensive phenotype. In addition, removal of ovarian sex hormones reduced adipose ACE2 activity and plasma Ang-(1-7) concentrations and resulted in robust obesity-induced hypertension. To understand whether obesity induced hypertension in ovariectomized (Ovx) females results from a loss of estrogen-mediated stimulation of ACE2, we chronically administered a physiological dose of estrogen to Ovx females (wild type, WT, and ACE2 deficient) fed a high fat (HF) diet. Administration of estrogen to WT Ovx females prevented the development of obesity hypertension which was associated with increased ACE2 mRNA abundance in adipose tissue, whereas the effect of estrogen on blood pressure was lost in Ovx females harboring ACE2 deficiency. Collectively, these results suggest estrogen protects female mice against obesity hypertension through stimulation of ACE2. Since numerous studies demonstrate that Ang-(1-7) functions to decrease blood pressure through Mas receptors (MasR), a logical next step is definition of the role of MasR on the development of obesity hypertension in female mice. The central hypothesis of this study is that estrogen stimulates ACE2 to increase Ang-(1-7) effects at MasR, protecting female mice from the development of obesity-hypertension. To test this hypothesis, we will define the effect of MasR deficiency on the development of obesity hypertension in female mice. Specific Aim: Define the effect of MasR deficiency on the development of HF dietinduced obesity and hypertension in female mice. We will determine the effect of low fat (LF) and HF diets on the development of obesity and hypertension in wild type and MasR deficient females. In addition, we will contrast effects of MasR deficiency on the development of obesity-hypertension in females to HF-fed male wild type mice. If MasR deficiency promotes the development of obesity-hypertension in female mice, we will also determine if estrogen restores protection of Ovx female mice fed a HF-diet from the development of obesity-hypertension through an Ang-(1-7)-MasR -dependent mechanism.
|Effective start/end date||7/1/14 → 6/30/15|
- American Heart Association Great Rivers Affiliate: $26,000.00
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