Sex hormones and cardiomyopathic phenotype induced by cardiac beta 2-adrenergic receptor overexpression.
Sex differences in cardiomyopathic phenotype and the role of gonadal status were studied in mice with cardiac overexpression of beta(2)-adrenergic receptors (ARs) over 6-15 months (mo) of age. Survival to 15 mo was 96% in wild-type mice but was poorer in transgenic (TG) mice and lower for males than females (13% vs. 56%, P < 0.001). Echocardiography demonstrated progressive left ventricular (LV) dilatation and reduction in LV fractional shortening in male but much less marked changes in female TG mice. Incidences of atrial thrombosis, pleural effusion and lung congestion were higher and myocyte size and fibrosis in the LV were greater in TG males than females. Deprivation of testicular hormones by castration during 3-15 mo of age improved survival and significantly ameliorated LV dysfunction, remodeling, and hypertrophy compared with intact TG males. No significant effect, except for a trend of a better survival, was detected by ovariectomy in TG females. In conclusion, cardiac beta(2)-AR overexpression at a high level leads to cardiomyopathy and heart failure with aging. Female mice had less cardiac remodeling, dysfunction, and pathology and a marked survival advantage over male mice, and this was independent of prevailing levels of ovarian hormones. TG males showed benefit from orchiectomy, suggesting a contribution by testicular hormones to the progression of the cardiomyopathic phenotype.
Gao
Xiao-Ming
XM
Baker Heart Research Institute and Alfred Heart Centre, Alfred Hospital, Melbourne, Victoria 8008, Australia.
Agrotis
Alex
A
Autelitano
Dominic J
DJ
Percy
Elodie
E
Woodcock
Elizabeth A
EA
Jennings
Garry L
GL
Dart
Anthony M
AM
Du
Xiao-Jun
XJ
D000728:Androgens / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000401:mortality / Q000503:physiopathology*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D006339:Heart Rate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012727:Sex Characteristics; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000401:mortality / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000235:genetics
D000728:Androgens; D004967:Estrogens; D018343:Receptors, Adrenergic, beta-2; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D018995:Myosin Heavy Chains