X inactivation regulates lymphocyte induced cardiac remodeling

After menopause, women lose the protective effect of female hormones and experience increased risk of adverse cardiac remodeling following myocardial infarction (MI). This may be due in part to the deleterious effects of genes encoded on the X chromosome. On average, 15% of genes located on the X chromosome escape inactivation in women, resulting in over expression. We hypothesize that with age T-cells escape X-chromosome inactivation (XCI), thus exacerbating the inflammatory response and resulting in adverse post-MI remodeling in women. We will use 2 aims to delineate a mechanism defining age effects on XCI and how this in turn influences T-cell mediated post-MI remodeling. Aim 1 will test the hypothesis that older females have an increased number of T-cells that escape XCI and exacerbate monocyte recruitment and activation post-MI. Aim 2 will test the hypothesis that female mice with T-cells that have escaped XCI will have adverse remodeling and decreased post-MI survival. Our understanding of sex differences especially the influence of sex chromosomes during post-MI remodeling and development of heart failure is lacking. The information obtained from the proposed experiments will have direct implications for medical management of women post-MI. Overall design: Myocardial infarction as induced in C57Bl6/J female mice by permanent occlusion of the left anterior descending artery ligation. At post-MI Day 5, cells were isolated from the infarct zone of young (3-5 months) and old (15-17 months old) and run for scRNA sequencing.

绝经后女性会丧失雌性激素的保护作用，心肌梗死（myocardial infarction, MI）后不良心脏重构的风险显著升高。该现象的部分原因可能是X染色体上编码基因所产生的有害作用。平均而言，X染色体上约15%的基因可在女性体内逃逸X染色体失活（X-chromosome inactivation, XCI），进而出现过表达。我们提出如下假说：随着年龄增长，T细胞会逃逸X染色体失活，进而加剧炎症反应，最终导致女性心肌梗死后出现不良心脏重构。本研究将通过两项研究目标，阐明年龄对X染色体失活的调控机制，以及该机制如何反过来影响T细胞介导的心肌梗死后心脏重构。目标1将验证如下假说：老年雌性个体体内逃逸X染色体失活的T细胞数量更多，会加剧心肌梗死后单核细胞的招募与活化过程。目标2将验证如下假说：T细胞逃逸X染色体失活的雌性小鼠会出现不良心脏重构，且心肌梗死后存活率降低。目前学界对性别差异的认识仍存在不足，尤其是在心肌梗死后重构与心力衰竭发生发展过程中，性染色体所发挥的调控作用尚未明确。本研究拟开展的实验所获得的结果，将对女性心肌梗死后的临床诊疗工作具有直接的指导意义。整体实验设计：通过永久性结扎左前降支动脉，在C57Bl6/J品系雌性小鼠中构建心肌梗死模型。在心肌梗死后第5天，从年轻（3~5月龄）与老年（15~17月龄）小鼠的梗死心肌区域分离细胞，开展单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）。