Abstract 15971: Epigenetic Control of Adult Cardiac Myocyte Proliferation
Cardiac myocyte (CM) proliferation is required for the heart regeneration seen in lower vertebrates and neonatal mammalian injury models. However, typically mammalian CMs stop proliferating soon after birth and subsequent heart growth comes from hypertrophy, limiting the adult heart’s regenerative potential after injury. The molecular events blocking CM proliferation in the adult heart remain poorly understood. We hypothesized that trimethylation of Lysine 9 of Histone H3 (H3K9me3), a histone modification associated with stable transcriptional repression, is required for the silencing of cell cycle genes in adult CMs (ACMs). To test this, we developed a transgenic (BiTg) mouse model where H3K9me3 is specifically removed by histone demethylase KDM4D in CMs. Loss of H3K9me3 in CMs disrupts ACM cell cycle gene silencing preferentially and results in increased CM cycling. Normalized heart mass was increased by postnatal day 14 (P14) and continued to increase until 9-weeks of age. ACM number, but not size, was increased in BiTg hearts, suggesting CM hyperplasia accounts for the increased heart mass. However, the heart growth ceased after 9 weeks, and cell cycle activity, though elevated in BiTg ACMs, was still much less than proliferative fetal CMs. This suggested that most H3K9me3-depleted ACMs were still able to exit the cell cycle. Depleting H3K9me3 did not affect heart function as mice with constitutive CM-specific KDM4D expression displayed normal heart function at 7-months. To determine if the BiTg ACMs had permanently exited the cell cycle (senescent) or were able to re-enter the cell cycle (quiescent), we challenged BiTg mice with a hypertrophic growth signal. Pressure-overload stimulated ACM mitotic activity and increases in ACM number in BiTg mice, in contrast to the hypertrophy-restricted growth in control ACMs. Thus, we demonstrated that H3K9me3 is required for cell cycle gene silencing in ACMs and depletion of H3K9me3 allows hyperplastic growth in vivo.
Author Disclosures: D. El-Nachef: None. K. Oyama: None. Y. Wu: None. Y. Liu: None. Y. Zhang: None. W. MacLellan: None.
- © 2016 by American Heart Association, Inc.