Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A.

Abstract

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-beta1, TGF-beta3, 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.

• Authors: Yuhao Li, Ichiro Kishimoto, Yoshihiko Saito, Masaki Harada, Koichiro Kuwahara, Takehiko Izumi, Ichiro Hamanaka, Nobuki Takahashi, Rika Kawakami, Keiji Tanimoto, Yasuaki Nakagawa, Michio Nakanishi, Yuichiro Adachi, David L Garbers, Akiyoshi Fukamizu, Kazuwa Nakao
• Journal: Endocrinology (Endocrinology) Vol. 145 Issue 2 Pg. 951-8 (Feb 2004) ISSN: 0013-7227 [Print] United States
• PMID: 14592959 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgen Receptor Antagonists
• Androgens
• Receptor, Angiotensin, Type 1
• Testosterone
• Flutamide
• Guanylate Cyclase
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Androgen Receptor Antagonists
• Androgens (physiology)
• Animals
• Blood Pressure
• Cardiomegaly (enzymology)
• Female
• Fibrosis
• Flutamide (pharmacology)
• Gene Deletion
• Gene Expression Profiling
• Guanylate Cyclase (deficiency, genetics, physiology)
• Male
• Mice
• Mice, Knockout
• Myocardium (pathology)
• Orchiectomy
• Ovariectomy
• Receptor, Angiotensin, Type 1 (deficiency, genetics, physiology)
• Receptors, Atrial Natriuretic Factor (deficiency, genetics, physiology)
• Sex Characteristics
• Testosterone (administration & dosage)