Female ClockΔ19/Δ19 mice are protected from the development of age-dependent cardiomyopathy
Female ClockΔ19/Δ19 mice are protected from the development of age-dependent cardiomyopathy
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DOI：
10.1093/cvr/cvx185
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发表时间：
2018-02-01
影响因子：
10.8
通讯作者：
Martino, Tami A.
中科院分区：
文献类型：
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作者：
Alibhai, Faisal J.;Reitz, Cristine J.;Martino, Tami A.
昼夜节律对健康的心血管生理是重要的，它们受分子昼夜节律机制的调节。之前，我们发现雄性Clock（Delta 19/Delta 19）小鼠中昼夜节律机制因子CLOCK的破坏导致年龄依赖性心肌病的发展。在这里，我们调查的作用，生物性别在防止心脏病在老龄化的女性时钟（德尔塔19/德尔塔19）mice.Methods和结果女性时钟（德尔塔19/德尔塔19）小鼠的心肌病的发展受到保护，随着年龄的增长，心脏结构和功能是类似的18个月的年龄与雌性WT小鼠。我们表明，与雌性WT相比，雌性Clock（Delta 19/Delta 19）小鼠保持正常的葡萄糖耐量。组织代谢谱显示，衰老的雌性Clock（Delta 19/Delta 19）小鼠保持正常的心脏葡萄糖摄取，而雄性Clock（Delta 19/Delta 19）小鼠具有与病理重构一致的增加的心脏葡萄糖摄取。鸟枪脂质组学揭示了性别和基因型特异性的磷脂差异，包括雄性Clock（Delta 19/Delta 19）小鼠中增加的心磷脂CL 76：11和减少的CL 72：8。此外，与雄性Clock（Delta 19/Delta 19）小鼠相比，雌性Clock（Delta 19/Delta 19）小鼠显示出AKT信号传导的激活增加和细胞色素c氧化酶活性保留，这有助于解释为什么它们免受心脏病的影响。为了确定这种保护如何发生在即使有时钟突变的女性中，我们检查了卵巢激素的影响。我们表明卵巢激素保护女性时钟（Delta 19/Delta 19）小鼠从心脏病作为卵巢切除雌性时钟（Delta 19/Delta 19）小鼠出现心脏扩张、葡萄糖耐受不良和心脏细胞色素c氧化酶减少;这种表型与在雄性Clock中观察到的年龄依赖性下降一致结论卵巢激素能保护雌性Clock（Delta 19/Delta 19）小鼠，即使Clock功能受到干扰，也能防止其发生年龄依赖性心肌病。了解心脏生长、更新和重塑中生物性别和昼夜节律机制的相互作用为理解和治疗心脏病打开了新的大门。
Aims Circadian rhythms are important for healthy cardiovascular physiology and they are regulated by the molecular circadian mechanism. Previously, we showed that disruption of the circadian mechanism factor CLOCK in male Clock(Delta 19/Delta 19) mice led to development of age-dependent cardiomyopathy. Here, we investigate the role of biological sex in protecting against heart disease in aging female Clock(Delta 19/Delta 19) mice.Methods and results Female Clock(Delta 19/Delta 19) mice are protected from the development of cardiomyopathy with age, as heart structure and function are similar to 18 months of age vs. female WT mice. We show that female Clock(Delta 19/Delta 19) mice maintain normal glucose tolerance as compared with female WT. Tissue metabolic profiling revealed that aging female Clock(Delta 19/Delta 19) mice maintain normal cardiac glucose uptake, whereas the male Clock(Delta 19/Delta 19) mice have increased cardiac glucose uptake consistent with pathological remodelling. Shotgun lipidomics revealed differences in phospholipids that were sex and genotype specific, including cardiolipin CL76: 11 that was increased and CL72: 8 that was decreased in male Clock(Delta 19/Delta 19) mice. Additionally, female Clock(Delta 19/Delta 19) mice show increased activation of AKT signalling and preserved cytochrome c oxidase activity compared with male Clock(Delta 19/Delta 19) mice, which can help to explain why they are protected from heart disease. To determine how this protection occurs in females even with the Clock mutation, we examined the effects of ovarian hormones. We show that ovarian hormones protect female Clock(Delta 19/Delta 19) mice from heart disease as ovariectomized female Clock(Delta 19/Delta 19) mice develop cardiac dilation, glucose intolerance and reduced cardiac cytochrome c oxidase; this phenotype is consistent with the age-dependent decline observed in male Clock(Delta 19/)Delta 19 mice.Conclusions These data demonstrate that ovarian hormones protect female Clock(Delta 19/Delta 19) mice from the development of age-dependent cardiomyopathy even though Clock function is disturbed. Understanding the interaction of biological sex and the circadian mechanism in cardiac growth, renewal and remodelling opens new doors for understanding and treating heart disease.