Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A.
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.
First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
Yuhao
Y
Li
Ichiro
I
Kishimoto
Yoshihiko
Y
Saito
Masaki
M
Harada
Koichiro
K
Kuwahara
Takehiko
T
Izumi
Ichiro
I
Hamanaka
Nobuki
N
Takahashi
Rika
R
Kawakami
Keiji
K
Tanimoto
Yasuaki
Y
Nakagawa
Michio
M
Nakanishi
Yuichiro
Y
Adachi
David L
DL
Garbers
Akiyoshi
A
Fukamizu
Kazuwa
K
Nakao
D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000201:enzymology*; D005260:Female; D005355:Fibrosis; D005485:Flutamide / Q000494:pharmacology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006162:Guanylate Cyclase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D009919:Orchiectomy; D010052:Ovariectomy; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012727:Sex Characteristics; D013739:Testosterone / Q000008:administration & dosage
D059002:Androgen Receptor Antagonists; D000728:Androgens; D044140:Receptor, Angiotensin, Type 1; D013739:Testosterone; D005485:Flutamide; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A