| First Author | Alibhai FJ | Year | 2017 |
| Journal | Cardiovasc Res | PubMed ID | 28927226 |
| Mgi Jnum | J:243739 | Mgi Id | MGI:5911508 |
| Doi | 10.1093/cvr/cvx185 | Citation | Alibhai FJ, et al. (2018) Female ClockDelta19/Delta19 mice are protected from the development of age-dependent cardiomyopathy. Cardiovasc Res 114(2):259-271 |
| abstractText | 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 ClockDelta19/Delta19 mice led to development of age-dependent cardiomyopathy. Here, we investigate the role of biological sex in protecting against heart disease in aging female ClockDelta19/Delta19 mice. Methods and results: Female ClockDelta19/Delta19 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 ClockDelta19/Delta19 mice maintain normal glucose tolerance as compared with female WT. Tissue metabolic profiling revealed that aging female ClockDelta19/Delta19 mice maintain normal cardiac glucose uptake, whereas the male ClockDelta19/Delta19 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 ClockDelta19/Delta19 mice. Additionally, female ClockDelta19/Delta19 mice show increased activation of AKT signalling and preserved cytochrome c oxidase activity compared with male ClockDelta19/Delta19 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 ClockDelta19/Delta19 mice from heart disease as ovariectomized female ClockDelta19/Delta19 mice develop cardiac dilation, glucose intolerance and reduced cardiac cytochrome c oxidase; this phenotype is consistent with the age-dependent decline observed in male ClockDelta19/Delta19 mice. Conclusions: These data demonstrate that ovarian hormones protect female ClockDelta19/Delta19 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. |
