The prevalence of obesity is rising in Kentucky and the nation. Prior to the obesity epidemic, hypertension prevalence was lower in females than males until menopause, when both obesity and hypertension increase. The most recent NHANES data demonstrate the surprising finding that the prevalence of hypertension is rising at a faster rate in females than males. This competing renewal focuses on mechanisms contributing to obesity-induced hypertension in males versus females, a highly significant topic since obesity is a primary cause of hypertension in both genders. We have examined whether an activated adipocyte renin-angiotensin system (RAS) is a link between obesity and hypertension. During the current period, we demonstrated that deficiency of adipocyte-derived angiotensinogen (AGT) prevented elevations in adipose and systemic angiotensin II (Ang II) concentrations and abolished the development of hypertension in obese male mice. We also demonstrated that adipocytes express angiotensin converting enzyme 2 (ACE2), which cleaves Ang II to form the vasodilator peptide, angiotensin-(1-7) (Ang-(1-7)). In male obese hypertensive mice exhibiting increased adipose-derived systemic Ang II, adipose ACE2 expression was reduced and systemic Ang-(1-7) concentrations plummeted. These results suggest that reductions in ACE2 in an expanded adipose mass make Ang II the predominant adipose-derived RAS peptide, contributing to hypertension in obese male mice. In contrast to males, 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. Removal of ovarian sex hormones reduced adipose ACE2 activity and plasma Ang- (1-7) concentrations and resulted in robust obesity-induced hypertension. Moreover, estrogen markedly stimulated ACE2 mRNA abundance in 3T3-L1 adipocytes. We hypothesize that differential regulation of adipocyte ACE2 in obese males versus females determines whether adipose tissue produces Ang II or Ang-(1- 7) in the development of hypertension.
Aim 1 tests the hypothesis that adipocyte ACE2 deficiency promotes hypertension in obese female mice, while ACE2 activation prevents hypertension in obese males through an adipocyte ACE2-dependent mechanism.
Aim 2 tests the hypothesis that estrogen promotes adipocyte ACE2 expression and protects male and ovariectomized female obese mice from hypertension.
Aim 3 tests the hypothesis that DIZE-induced ACE2 activation reduces blood pressure in male and ovariectomized female obese hypertensive mice through an Ang-(1-7)/MasR-dependent mechanism. The impact of these studies is definition of mechanisms for the development of hypertension in obese males versus females. We will also develop ACE2 activation as a novel therapy to treat hypertension in obese males and/or menopausal females.

Public Health Relevance

Obesity is at epidemic proportions in the US, and may eventually overcome previously ascribed protection of females against the development of hypertension. These studies focus on the renin-angiotensin system of adipocytes as a mediator of obesity-hypertension in males versus females. Since obesity is the primary cause of hypertension in the US, and the prevalence of hypertension is increasing more rapidly in females than males, our studies will define mechanisms for these differences and uncover novel targets for drug therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL073085-10A1
Application #
8710869
Study Section
Special Emphasis Panel (ZRG1-VH-F (02))
Program Officer
OH, Youngsuk
Project Start
2003-06-03
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
10
Fiscal Year
2014
Total Cost
$384,687
Indirect Cost
$128,229
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Narayanaswami, Vidya; Dwoskin, Linda P (2016) Obesity: Current and potential pharmacotherapeutics and targets. Pharmacol Ther :
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