Sex-Specific mTOR Signaling Determines Sexual Dimorphism in Myocardial Adaptation in Normotensive DOCA-Salt Model
Sex-Specific mTOR Signaling Determines Sexual Dimorphism in Myocardial Adaptation in Normotensive DOCA-Salt Model
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DOI：
10.1161/hypertensionaha.111.00276
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发表时间：
2013-03-01
期刊：
影响因子：
8.3
通讯作者：
Dragun, Duska
中科院分区：
文献类型：
--
作者：
Guergen, Dennis;Kusch, Angelika;Dragun, Duska
醋酸脱氧皮质酮（DOCA）-盐小鼠模型在雄性小鼠中表现出不利的心脏重塑，在雌性小鼠中表现出心脏保护作用，即使血压正常化。我们假设，完整的哺乳动物雷帕霉素靶蛋白（mTOR）信号传导是女性心脏保护所必需的。我们首先在野生型小鼠中测试了雷帕霉素靶向mTOR后的性别差异和细胞内信号传导。无线电遥测血压保持正常6周。在雄性小鼠中，雷帕霉素显著降低左心室肥大，保持射血分数，抑制纤维化，并维持毛细血管结构。与溶剂对照组相比，雷帕霉素处理的雄性小鼠中检测到mTORC 1活性降低和mTORC 2活性增加。相比之下，雌性小鼠发生扩张性左心室肥大、心脏纤维化和毛细血管损失，类似于我们先前描述的缺乏雌激素受体β（ER β（-/-））的DOCA盐雌性小鼠。由于雷帕霉素下调雌性小鼠的ER β，我们接下来研究了ER β（-/-）血压正常的DOCA-盐雌性小鼠。溶剂处理的野生型雌性动物对DOCA盐的反应维持其高组成性mTORC 1和mTORC 2。与雄性相比，雷帕霉素使两种mTORC均降低，特别是mTORC 2降低60%。ER β（-/-）DOCA盐雌性动物显示出相似的mTORC 1和mTORC 2反应模式。我们认为ER β依赖性调节涉及mTOR信号分支的性别特异性使用。mTORC 1和mTORC 2信号的维持似乎是女性适应性心脏重塑的关键，并支持左心室肥大性别特异性治疗策略的基本原理。（高血压。2013; 61：730-736）。circle在线数据补充
The deoxycorticosterone acetate (DOCA)-salt mouse model exhibits adverse cardiac remodeling in male mice and cardiac protection in female mice, even when blood pressure is normalized. We hypothesized that intact mammalian target of rapamycin (mTOR) signaling is necessary for cardiac protection in females. We first tested sex differences and intracellular signaling after mTOR targeting with rapamycin in wild-type mice. Radio-telemetric blood pressure was maintained at normal for 6 weeks. Rapamycin significantly reduced left ventricular hypertrophy, preserved ejection fraction, inhibited fibrosis, and maintained capillary structure in male mice. Decreased mTORC1 and increased mTORC2 activity were detected in rapamycin-treated male mice compared with vehicle controls. In contrast, female mice developed dilative left ventricular hypertrophy, cardiac fibrosis, and capillary loss similar to DOCA-salt females lacking the estrogen receptor beta (ER beta(-/-)) that we described earlier. Because rapamycin downregulated ER beta in female mice, we next studied ER beta(-/-) normotensive DOCA-salt females. Vehicle-treated wild-type females maintained their high constitutive mTORC1 and mTORC2 in response to DOCA-salt. In contrast to males, both mTORCs were decreased by rapamycin, in particular mTORC2 by 60%. ER beta(-/-) DOCA-salt females showed similar mTORC1 and mTORC2 response patterns. We suggest that ER beta-dependent regulation involves sex-specific use of mTOR signaling branches. Maintenance of both mTORC1 and mTORC2 signaling seems to be essential for adaptive cardiac remodeling in females and supports a rationale for sex-specific therapeutic strategies in left ventricular hypertrophy. (Hypertension. 2013; 61: 730-736.) circle Online Data Supplement