Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China.
Chongqing Institute of Cardiology, Chongqing, China.
Cell Prolif. 2020 Nov;53(11):e12910. doi: 10.1111/cpr.12910. Epub 2020 Oct 12.
The mechanisms responsible for the postnatal loss of mammalian cardiac regenerative capacity are not fully elucidated. The aim of the present study is to investigate the role of progesterone in cardiac regeneration and explore underlying mechanism.
Effect of progesterone on cardiomyocyte proliferation was analysed by immunofluorescent staining. RNA sequencing was performed to screen key target genes of progesterone, and yes-associated protein (YAP) was knocked down to demonstrate its role in pro-proliferative effect of progesterone. Effect of progesterone on activity of YAP promoter was measured by luciferase assay and interaction between progesterone receptor and YAP promoter by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). Adult mice were subjected to myocardial infarction, and then, effects of progesterone on adult cardiac regeneration were analysed.
Progesterone supplementation enhanced cardiomyocyte proliferation in a progesterone receptor-dependent manner. Progesterone up-regulated YAP expression and knockdown of YAP by small interfering RNA reduced progesterone-mediated cardiomyocyte proliferative effect. Progesterone receptor interacted with the YAP promoter, determined by ChIP and EMSA; progesterone increased luciferase activity of YAP promoter and up-regulated YAP target genes. Progesterone administration also promoted adult cardiomyocyte proliferation and improved cardiac function in myocardial infarction.
Our data uncover a role of circulating progesterone withdrawal as a novel mechanism for the postnatal loss of mammalian cardiac regenerative potential. Progesterone promotes both neonatal and adult cardiomyocyte proliferation by up-regulating YAP expression.
负责哺乳动物心脏再生能力的产后丧失的机制尚未完全阐明。本研究旨在探讨孕激素在心脏再生中的作用，并探讨其潜在机制。
通过免疫荧光染色分析孕激素对心肌细胞增殖的影响。进行 RNA 测序以筛选孕激素的关键靶基因，并用 YAP 敲低来证明其在孕激素促增殖作用中的作用。通过荧光素酶测定测量孕激素对 YAP 启动子活性的影响，通过电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）测定孕激素受体与 YAP 启动子之间的相互作用。成年小鼠进行心肌梗死，然后分析孕激素对成年心脏再生的影响。
孕激素补充以孕激素受体依赖的方式增强心肌细胞增殖。孕激素上调 YAP 表达，用小干扰 RNA 敲低 YAP 可降低孕激素介导的心肌细胞增殖作用。通过 ChIP 和 EMSA 确定孕激素受体与 YAP 启动子相互作用；孕激素增加 YAP 启动子的荧光素酶活性并上调 YAP 靶基因。孕激素给药还可促进成年心肌细胞增殖并改善心肌梗死后的心脏功能。
我们的数据揭示了循环孕激素撤退作为哺乳动物心脏再生潜力产后丧失的新机制。孕激素通过上调 YAP 表达促进新生儿和成年心肌细胞增殖。
