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Androgen Contributes to Gender-Related Cardiac Hypertrophy and Fibrosis in Mice Lacking the Gene Encoding Guanylyl Cyclase-A

Department of Medicine and Clinical Science (Y.L., I.K., Y.S., M.H., K.K., T.I., I.H., N.T., R.K., K.T., Y.N., M.N., Y.A., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Howard Hughes Medical Institute and Department of Pharmacology (D.L.G.), University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas 75390; and Center for Tsukuba Advanced Research Alliance (A.F.), Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan

Address all correspondence and requests for reprints to: Yoshihiko Saito, First Department of Internal Medicine, Nara Medical University, 840, Shijo-cho, Kashihara, Nara 634-8522, Japan. E-mail: yssaito{at}naramed-u.ac.jp.

Myocardial hypertrophy and extended cardiac fibrosis are independent risk factors for congestive heart failure and sudden cardiac death. Before age 50, men are at greater risk for cardiovascular disease than age-matched women. In the current studies, we found that cardiac hypertrophy and fibrosis were significantly more pronounced in males compared with females of guanylyl cyclase-A knockout (GC-A KO) mice at 16 wk of age. These gender-related differences were not seen in wild-type mice. In the further studies, either castration (at 10 wk of age) or flutamide, an androgen receptor antagonist, markedly attenuated cardiac hypertrophy and fibrosis in male GC-A KO mice without blood pressure change. In contrast, ovariectomy (at 10 wk of age) had little effect. Also, chronic testosterone infusion increased cardiac mass and fibrosis in ovariectomized GC-A mice. None of the treatments affected cardiac mass or the extent of fibrosis in wild-type mice. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, TGF-ß1, TGF-ß3, angiotensinogen, and angiotensin converting enzyme in the ventricles of male GC-A KO mice was substantially decreased by castration. The gender differences were virtually abolished by targeted deletion of the angiotensin II type 1A receptor gene (AT1A). Neither castration nor testosterone administration induced any change in the cardiac phenotypes of double-KO mice for GC-A and AT1A. Thus, we suggest that androgens contribute to gender-related differences in cardiac hypertrophy and fibrosis by a mechanism involving AT1A receptors and GC-A.

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