Angiotensin Converting Enzyme 2 Contributes to Sex Differences in the Development of Obesity Hypertension in C57BL/6 Mice

Abstract

Objective Obesity promotes hypertension, but it is unclear if sex differences exist in obesity-related hypertension. Angiotensin converting enzyme 2 (ACE2) converts angiotensin II (AngII) to angiotensin-(1–7) (Ang-[1–7]), controlling peptide balance. We hypothesized that tissue-specific regulation of ACE2 by high-fat (HF) feeding and sex hormones contributes to sex differences in obesity-hypertension. Methods and Results HF-fed females gained more body weight and fat mass than males. HF-fed males exhibiting reduced kidney ACE2 activity had increased plasma angiotensin II levels and decreased plasma Ang-(1–7) levels. In contrast, HF-fed females exhibiting elevated adipose ACE2 activity had increased plasma Ang-(1–7) levels. HF-fed males had elevated systolic and diastolic blood pressure that were abolished by losartan. In contrast, HF-fed females did not exhibit increased systolic blood pressure until females were administered the Ang-(1–7) receptor antagonist, D-Ala-Ang-(1–7). Deficiency of ACE2 increased systolic blood pressure in HF-fed males and females, which was abolished by losartan. Ovariectomy of HF-fed female mice reduced adipose ACE2 activity and plasma Ang-(1–7) levels, and promoted obesity-hypertension. Finally, estrogen, but not other sex hormones, increased adipocyte ACE2 mRNA abundance. Conclusions These results demonstrate that tissue-specific regulation of ACE2 by diet and sex hormones contributes to sex differences in obesity-hypertension.

Administration of 17β-estradiol to ovariectomized obese female mice reverses obesity-hypertension through an ACE2-dependent mechanism

“…17␤-Estradiol (E 2 ) has been reported to regulate ACE2 expression both in vitro and in vivo (15,20,21). Moreover, results from our laboratory demonstrated that E 2 increases ACE2 mRNA abundance in adipocytes (15).…”

“…Ovariectomy of HF-fed female mice reduced adipose ACE2 expression and plasma ANG-(1-7) concentrations and converted female mice to an obesity-hypertension phenotype (15). These results suggest that sexual dimorphism of obesity-hypertension may be associated with ACE2-mediated regulation of the ANG II/ANG-(1-7) balance, and that adipose ACE2 may contribute significantly to regulation of the balance of these vasoactive peptides.17␤-Estradiol (E 2 ) has been reported to regulate ACE2 expression both in vitro and in vivo (15,20,21). Moreover, results from our laboratory demonstrated that E 2 increases ACE2 mRNA abundance in adipocytes (15).…”

“…Adipocytes express several components of the RAS necessary to synthesize, respond to, or metabolize ANG II. In male mice with dietinduced obesity-hypertension associated with increased plasma and adipose ANG II concentrations, adipose expression of angiotensin-converting enzyme 2 (ACE2) (14), which metabolizes ANG II to form angiotensin-(1-7) [ANG-(1-7)], was reduced, and plasma ANG-(1-7) concentrations plummeted to levels of ACE2-deficient mice (15). In contrast, female mice made obese from consumption of a high-fat (HF) diet did not exhibit changes in plasma ANG II concentrations and were resistant to the development of obesity-induced hypertension (15).…”

“…In male mice with dietinduced obesity-hypertension associated with increased plasma and adipose ANG II concentrations, adipose expression of angiotensin-converting enzyme 2 (ACE2) (14), which metabolizes ANG II to form angiotensin-(1-7) [ANG-(1-7)], was reduced, and plasma ANG-(1-7) concentrations plummeted to levels of ACE2-deficient mice (15). In contrast, female mice made obese from consumption of a high-fat (HF) diet did not exhibit changes in plasma ANG II concentrations and were resistant to the development of obesity-induced hypertension (15). Moreover, protection against obesity-hypertension in females was associated with increased adipose ACE2 expression and elevated plasma concentrations of the vasodilator ANG-(1-7) (15).…”

Protecting the Heart in Obesity: Role of ACE2 and Its Partners

“…disease (17). Further studies exploring the relationship between epicardial adipose tissue, the RAAS, and cardiomyopathy in female models of obesity may shed light on why heart failure with a preserved ejection fraction is more common in obese women.…”