This Article Free upon publication Full Text Full Text (PDF) All Versions of this Article: 51/4/1177    most recent HYPERTENSIONAHA.107.107938v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Karatas, A. Articles by Dragun, D. PubMed PubMed Citation Articles by Karatas, A. Articles by Dragun, D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Hazardous Substances DB HYDRALAZINE HYDROCHLORIDE Related Collections Cardio-renal physiology/pathophysiology Other hypertension Hypertrophy Animal models of human disease Physiological and pathological control of gene expression

(Hypertension. 2008;51:1177.)
© 2008 American Heart Association, Inc.

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Deoxycorticosterone Acetate-Salt Mice Exhibit Blood Pressure–Independent Sexual Dimorphism

Aysun Karatas; Björn Hegner; Leon J. de Windt; Friedrich C. Luft; Carola Schubert; Volkmar Gross; Yoshihiro J. Akashi; Dennis Gürgen; Ulrich Kintscher; Andrey C. da Costa Goncalves; Vera Regitz-Zagrosek; Duska Dragun

From the Department of Nephrology and Intensive Care, Medicine Campus (A.K., B.H., D.G., D.D.), Virchow-Klinikum, Berlin, Germany; Center for Cardiovascular Research (A.K., B.H., C.S., Y.J.A., D.G., U.K., V.R-Z., D.D.), Medical Faculty of the Charité, Berlin, Germany; Hubrecht Laboratory and Interuniversity Cardiology Institute (L.J.d.W.), Utrecht, The Netherlands; and Experimental and Clinical Research Center (F.C.L., V.G., A.C.d.C.G.), Max-Delbrück Center for Molecular Medicine and HELIOS Klinikum, Berlin, Germany.

Correspondence to Duska Dragun, Department of Nephrology and Intensive Care Medicine, Charité Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail duska.dragun{at}charite.de

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 Aβ and for myocyte-enriched calcineurin interacting protein 1 were upregulated in male but not in female mice. Enhanced activity of calcineurin Aβ, 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-β. 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.

Key Words: heart • kidney • hypertrophy • inflammation • fibrosis • calcineurin • MCIP1 • NFATc2