Angiotensin converting enzyme 2 contributes to sex differences in the development of obesity hypertension in C57BL/6 mice

Arterioscler Thromb Vasc Biol. 2012 Jun;32(6):1392-9. doi: 10.1161/ATVBAHA.112.248559. Epub 2012 Mar 29.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / enzymology
  • Adiposity
  • Angiotensin I / blood
  • Angiotensin II / blood
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Blood Pressure* / drug effects
  • Diet, High-Fat
  • Disease Models, Animal
  • Estrogens / metabolism
  • Female
  • Gene Expression Regulation, Enzymologic
  • Hypertension / drug therapy
  • Hypertension / enzymology
  • Hypertension / etiology*
  • Hypertension / genetics
  • Hypertension / physiopathology
  • Losartan / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / complications*
  • Obesity / enzymology
  • Obesity / etiology
  • Obesity / genetics
  • Obesity / physiopathology
  • Ovariectomy
  • Peptide Fragments / blood
  • Peptidyl-Dipeptidase A / deficiency
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism*
  • Progesterone / metabolism
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism
  • RNA, Messenger / metabolism
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / metabolism
  • Risk Factors
  • Sex Factors
  • Testosterone / metabolism
  • Time Factors
  • Weight Gain

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Estrogens
  • Peptide Fragments
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Angiotensin II
  • Testosterone
  • Progesterone
  • Angiotensin I
  • Peptidyl-Dipeptidase A
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)
  • Losartan