title: 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.
  
  
  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.
authors.affiliation: Graduate Center for Nutritional Sciences, University of Kentucky, Room 521b, Wethington Building, 900 S. Limestone, Lexington, KY 40536-0200, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Gupte
authors.forename: Sean E
authors.initials: SE
authors.lastname: Thatcher
authors.forename: Carine M
authors.initials: CM
authors.lastname: Boustany-Kari
authors.forename: Robin
authors.initials: R
authors.lastname: Shoemaker
authors.forename: Frederique
authors.initials: F
authors.lastname: Yiannikouris
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Karounos
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000201:enzymology; D050154:Adiposity; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D010052:Ovariectomy; D010446:Peptide Fragments / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D012307:Risk Factors; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors; D015430:Weight Gain
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004967:Estrogens; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D013739:Testosterone; D011374:Progesterone; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D019808:Losartan