Yusifov Aykhan, Chhatre Vikram E, Koplin Eva K, Wilson Cortney E, Schmitt Emily E, Woulfe Kathleen C, Bruns Danielle R
Kinesiology and Health, University of Wyoming, Laramie, WY, USA.
WY INBRE Bioinformatics/Data Science Core, Laramie, WY, USA.
Physiol Rep. 2021 Jul;9(13):e14940. doi: 10.14814/phy2.14940.
Risk for heart disease increases with advanced age and differs between sexes, with females generally protected from heart disease until menopause. Despite these epidemiological observations, the molecular mechanisms that underlie sex-specific differences in cardiac function have not been fully described. We used high throughput transcriptomics in juvenile (5 weeks), adult (4-6 months), and aged (18 months) male and female mice to understand how cardiac gene expression changes across the life course and by sex. While male gene expression profiles differed between juvenile-adult and juvenile-aged (254 and 518 genes, respectively), we found no significant differences in adult-aged gene expression. Females had distinct gene expression changes across the life course with 1835 genes in juvenile-adult and 1328 in adult-aged. Analysis of differentially expressed genes (DEGs) suggests that juvenile to adulthood genes were clustered in cell cycle and development-related pathways in contrast to adulthood-aged which were characterized by immune-and inflammation-related pathways. Analysis of sex differences within each age suggests that juvenile and aged cardiac transcriptomes are different between males and females, with significantly fewer DEGs identified in adult males and females. Interestingly, the male-female differences in early age were distinct from those in advanced age. These findings are in contrast to expected sex differences historically attributed to estrogen and could not be explained by estrogen-direct mechanisms alone as evidenced by juvenile sexual immaturity and reproductive incompetence in the aged mice. Together, distinct trajectories in cardiac transcriptomic profiles highlight fundamental sex differences across the life course and demonstrate the need for the consideration of age and sex as biological variables in heart disease.
心脏病风险随年龄增长而增加，且存在性别差异，女性在绝经前通常对心脏病具有一定的保护作用。尽管有这些流行病学观察结果，但心脏功能性别特异性差异背后的分子机制尚未得到充分描述。我们对幼年（5周龄）、成年（4 - 6月龄）和老年（18月龄）的雄性和雌性小鼠进行了高通量转录组学研究，以了解心脏基因表达如何随生命历程和性别而变化。虽然雄性基因表达谱在幼年 - 成年和幼年 - 老年之间存在差异（分别为254个和518个基因），但我们发现成年 - 老年基因表达没有显著差异。雌性在整个生命历程中具有明显的基因表达变化，幼年 - 成年有1835个基因，成年 - 老年有1328个基因。对差异表达基因（DEG）的分析表明，幼年到成年的基因聚集在细胞周期和发育相关途径中，而成年到老年的基因则以免疫和炎症相关途径为特征。对每个年龄段内性别差异的分析表明，幼年和老年心脏转录组在雄性和雌性之间存在差异，成年雄性和雌性中鉴定出的DEG明显较少。有趣的是，幼年时的雌雄差异与老年时不同。这些发现与历史上归因于雌激素的预期性别差异相反，并且不能仅由雌激素直接机制来解释，如幼年小鼠性不成熟和老年小鼠生殖无能所证明的那样。总之，心脏转录组谱的不同轨迹突出了整个生命历程中的基本性别差异，并表明在心脏病研究中需要将年龄和性别作为生物学变量加以考虑。
