Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A
Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A
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DOI：
10.1210/en.2003-0816
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发表时间：
2004-02-01
期刊：
影响因子：
4.8
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Li, YH;Kishimoto, I;Nakao, K
心肌肥厚和广泛的心脏纤维化是充血性心力衰竭和心源性猝死的独立危险因素。在50岁之前，男性患心血管疾病的风险高于同龄女性。在目前的研究中，我们发现，在16周龄时，鸟苷酸环化酶-A敲除（GC-A KO）小鼠的雄性与雌性相比，心脏肥大和纤维化明显更明显。这些与性别相关的差异在野生型小鼠中没有观察到。在进一步的研究中，去势（10周龄）或雄激素受体拮抗剂氟替卡松，显着减弱雄性GC-A KO小鼠的心脏肥大和纤维化，而血压没有变化。相比之下，卵巢切除术（在10周龄）几乎没有影响。此外，慢性睾酮输注增加卵巢切除GC-A小鼠的心脏质量和纤维化。这些治疗都没有影响野生型小鼠的心脏质量或纤维化程度。去势显著降低了雄性GC-AKO小鼠心室中编码心房利钠肽、脑利钠肽、胶原蛋白I和III、TGF-β 1、TGF-β 3、血管紧张素原和血管紧张素转换酶的mRNA的过表达。通过靶向删除血管紧张素II 1A型受体基因（AT 1A），几乎消除了性别差异。去势或睾酮给药均未诱导GC-A和AT 1A双KO小鼠心脏表型的任何变化。因此，我们认为雄激素通过一种涉及AT 1A受体和GC-A的机制导致了心脏肥大和纤维化的性别差异。
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-AKO 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.