Background: KDM6A mediates the removal of repressive trimethylation from H3K27me3 to activate target gene expression. It is not known, however, whether KDM6A plays a role in the regulation of cardiac aging. We hypothesized that cardiac-specific KDM6A knockout accelerates cardiac aging.
Methods and
Results: Aging decreased histone demethylase KDM6A expression and activity in human cardiomyocytes. Downregulation of KDM6A expression was also found in cardiomyocytes of aged mice. The cardiomyocytes-specific KDM6A knockout (Myh6-KDM6A cKO) mouse model was created by using Cre-LoxP system. KDM6A deletion didn’t cause overt cardiac remodeling and dysfunction in normal condition. However, cardiomyocytes-specific conditional knockout of KDM6A exaggerated ISO-induced cardiac dysfunction and cardiac remodeling. Moreover, Myh6-KDM6A cKO mice showed early cardiac aging at 23-month-old, while control mice didn’t display cardiac aging until 27-month-old. Therefore, KDM6A deletion accelerated cardiac aging. ChiP-Seq analysis revealed candidate transcription factors participating in KDM6A cKO-induced cardiac aging. In particular, HoxC4 was down-regulated in the cardiomyocytes of Myh6-KDM6A cKO mice. Knockdown of HoxC4 gene in H9c2 cardiomyoblast cell line caused ER stress. The ER stress further resulted in oxidative stress and cardiomyocytes apoptosis in cardiomyocytes-specific conditional knockout of KDM6A mice.
Conclusions: Cardiomyocytes-specific conditional knockout of KDM6A causes cardiac aging through induction of HoxC4-mediated ER stress. These observations suggest KDM6A a potential therapeutic target for cardiac aging.
This work was supported by NIH R01AG049780, R01AG062375 and R01HL154147.
