Sex disparities in cardiac homeostasis and heart disease are well documented, with differences attributed to actions of sex hormones. However, studies have indicated sex chromosomes act outside of the gonads to function without mediation by gonadal hormones. Here, we performed transcriptional and proteomics profiling to define differences between male and female mouse hearts. We demonstrate, contrary to current dogma, cardiac sex disparities are controlled not only by sex hormones but also through a sex-chromosome mechanism. Using Turner syndrome (XO) and Klinefelter (XXY) models, we find the sex-chromosome pathway is established by X-linked gene dosage. We demonstrate cardiac sex disparities occur at the earliest stages of heart formation, a period before gonad formation. Using these datasets, we identify and define a role for alpha-1B-glycoprotein (A1BG), showing loss of A1BG leads to cardiac defects in females, but not males. These studies provide resources for studying sex-biased cardiac disease states.

心脏稳态和心脏病的性别差异有据可查，差异归因于性激素的作用。然而，研究表明，性染色体在性腺之外起作用，无需性腺激素的调节即可发挥作用。在这里，我们进行了转录和蛋白质组学分析，以确定雄性和雌性小鼠心脏之间的差异。我们证明，与目前的教条相反，心脏性别差异不仅受性激素控制，还受性染色体机制控制。使用特纳综合征 (XO) 和 Klinefelter (XXY) 模型，我们发现性染色体通路是由 X 连锁基因剂量建立的。我们证明心脏性别差异发生在心脏形成的最早阶段，即性腺形成之前的时期。使用这些数据集，我们确定并定义了 alpha-1B-糖蛋白 (A1BG) 的作用，表明 A1BG 的缺失会导致女性而非男性的心脏缺陷。这些研究为研究性别偏见的心脏病状态提供了资源。