Gao Xiao-Ming, Agrotis Alex, Autelitano Dominic J, Percy Elodie, Woodcock Elizabeth A, Jennings Garry L, Dart Anthony M, Du Xiao-Jun
Baker Heart Research Institute and Alfred Heart Centre, Alfred Hospital, Melbourne, Victoria 8008, Australia.
Endocrinology. 2003 Sep;144(9):4097-105. doi: 10.1210/en.2002-0214.
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.
在6至15个月龄时心脏过表达β₂-肾上腺素能受体（AR）的小鼠中，研究了心肌病表型的性别差异以及性腺状态的作用。野生型小鼠15个月龄时的存活率为96%，但转基因（TG）小鼠的存活率较低，且雄性低于雌性（13%对56%，P<0.001）。超声心动图显示雄性TG小鼠左心室（LV）逐渐扩张，左心室缩短分数降低，而雌性TG小鼠的变化则不那么明显。TG雄性小鼠的心房血栓形成、胸腔积液和肺充血发生率更高，左心室的心肌细胞大小和纤维化程度也比雌性更严重。在3至15个月龄时进行阉割去除睾丸激素，与完整的TG雄性小鼠相比，可提高存活率，并显著改善左心室功能障碍、重塑和肥大。TG雌性小鼠卵巢切除术后，除了有更好的存活趋势外，未检测到显著影响。总之，高水平的心脏β₂-AR过表达会导致衰老相关的心肌病和心力衰竭。雌性小鼠的心脏重塑、功能障碍和病理变化较少，比雄性小鼠有明显的存活优势，且这与卵巢激素的现有水平无关。TG雄性小鼠从睾丸切除术中获益，表明睾丸激素对心肌病表型的进展有影响。
