Progesterone, via yes‐associated protein, promotes cardiomyocyte proliferation and cardiac repair

Abstract

Objectives 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. Materials and Methods 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. Results 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. Conclusion 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.

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

“…Recently, progesterone has emerged as a mediator of sex-dependent transcriptional programs during cardiomyocyte maturation (171). Interestingly, progesterone supplementation has been suggested to increase cardiomyocyte proliferation and heart regeneration after myocardial infarction in a progesterone receptor-dependent manner, by increasing YAP expression and signaling (172).…”

Progesterone Receptor Modulates Extraembryonic Mesoderm and Cardiac Progenitor Specification during Mouse Gastrulation

“…Thus, PGR could have an inhibitory effect on cardiac muscle cells originating from the SHF 57 . Again postnatally, progesterone supplementation promotes neonatal cardiomyocytes proliferation through the upregulation of YAP signaling [ 56 ]. Thus, PGR could promote cardiomyocyte formation.…”

Evaluation of the Interaction of Sex Hormones and Cardiovascular Function and Health

“…The effects of progestogens in the cardiovascular system have not been studied extensively and further research is required to elucidate precise effects in this context. Thus far, progesterone was shown to increase β-oxidation and proliferation in cardiomyocytes [ 79 , 80 ]. Moreover, stimulation of vasorelaxation of ECs and VSMCs were found, through increased eNOS activity and altered calcium availability via increased sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) expression and activity [ 81 – 83 ].…”