title: Deoxycorticosterone acetate-salt mice exhibit blood pressure-independent sexual dimorphism.
abstract: We tested the hypothesis that female and male mice differ in terms of cardiac hypertrophy after deoxycorticosterone acetate (DOCA)+salt hypertension (uninephrectomy and 1% saline in drinking water) and focused on calcineurin signaling. We excluded confounding effects of blood pressure elevation or sex-related blood pressure differences by treating DOCA-salt mice with hydralazine (250 mg/L in drinking water). We found that directly measured mean arterial blood pressure was lowered to control values with hydralazine and corroborated this finding in separate mouse groups with radiotelemetry. Male mice were more responsive to DOCA-salt-related effects. They developed more left ventricular hypertrophy and more renal hypertrophy after 6 weeks of DOCA-salt+hydralazine compared with female mice. In hearts, transcripts for calcineurin Abeta and for myocyte-enriched calcineurin interacting protein 1 were upregulated in male but not in female mice. Enhanced activity of calcineurin Abeta, as indicated by diminished phosphorylation of NFATc2 in male mice, accounted for this sex-specific difference. Stretch-related, inflammatory, and profibrotic responses were also accentuated in male mice, as shown by higher transcript levels of atrial natriuretic peptide, monocyte chemoattractant protein-1, and transforming growth factor-beta. Our results support sex-specific regulation of the calcineurin pathway in response to largely blood pressure-independent mineralocorticoid action. We suggest that sex-specific calcineurin activation determines the maladaptive cardiac and renal hypertrophic responses and accompanying organ injury in male mice.
authors.affiliation: Department of Nephrology and Intensive Care, Medicine Campus, Virchow-Klinikum, Berlin, Germany.
authors.forename: Aysun
authors.initials: A
authors.lastname: Karatas
authors.forename: Björn
authors.initials: B
authors.lastname: Hegner
authors.forename: Leon J
authors.initials: LJ
authors.lastname: de Windt
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Carola
authors.initials: C
authors.lastname: Schubert
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
authors.forename: Yoshihiro J
authors.initials: YJ
authors.lastname: Akashi
authors.forename: Dennis
authors.initials: D
authors.lastname: Gürgen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.forename: Andrey C
authors.initials: AC
authors.lastname: da Costa Goncalves
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D019703:Calcineurin / Q000378:metabolism; D003900:Desoxycorticosterone / Q000494:pharmacology*; D004452:Echocardiography; D005260:Female; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008901:Mineralocorticoids / Q000494:pharmacology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D008901:Mineralocorticoids; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D017673:Sodium Chloride, Dietary; D006830:Hydralazine; D003900:Desoxycorticosterone; D019703:Calcineurin