Key result
Combined ANP and DN-FOXO promotes cardiomyocyte proliferation and reduces post-MI scarring in mice.
Why the study?
The molecular mechanisms by which natriuretic peptides and Forkhead O transcription factors cooperatively regulate cardiomyocyte cell cycle re-entry during early postnatal life are poorly understood.
p-value: p=<0.01
Natriuretic peptides and FOXO transcription factors cooperatively promote cardiomyocyte cell cycle re-entry and cardiac repair in postnatal mice.
Hypothesis-generating for ANP-FOXO-mediated cardiomyocyte regeneration post-MI; requires validation in adult models before clinical consideration.
BACKGROUND: Cardiomyocytes proliferate rapidly during fetal life but lose their ability of proliferation soon after birth. However, before terminal withdrawal from the cell cycle, cardiomyocytes undergo another round of cell cycle during early postnatal life in mice. While a transient wave of increased DNA synthesis in cardiomyocyte has been observed in postnatal mouse hearts, the molecular mechanisms describing cardiomyocyte cell cycle re-entry remain poorly understood. Atrial and B-type natriuretic peptides (ANP and BNP) are abundantly expressed in embryonic heart ventricles. After birth, the expression of both genes is strongly reduced in the ventricular myocardium. Forkhead O (FOXO) transcription factors are expressed in both embryonic and postnatal heart ventricles. Their transcriptional activity negatively affects cardiomyocyte proliferation. Upon phosphorylation, FOXO is translocated to the cytoplasm and is transcriptionally inactive. Despite these important findings, it remains largely unknown whether natriuretic peptides and FOXO cooperatively play a role in regulating cardiomyocyte cell cycle activity during early postnatal life. RESULTS: We observed that the expression of ANP and BNP and the level of phosphorylated FOXO were transiently increased in the postnatal mouse heart ventricles, which coincided with the burst of cardiomyocyte cell cycle re-entry during early postnatal life in mice. Cell culture studies showed that ANP/BNP signaling and FOXO cooperatively promoted cell cycle activity in neonatal mouse cardiomyocytes. The enhanced cell cycle activity observed in combined treatment of ANP/BNP and dominant-negative FOXO (DN-FOXO), which can bind FOXO recognition sites on DNA but cannot activate transcription, was primarily mediated through natriuretic peptide receptor 3 (Npr3). In mice, simultaneous application of ANP and DN-FOXO in postnatal hearts reactivated cell cycle in cardiomyocytes, resulting in reduced scar formation after experimental myocardial infarction. CONCLUSIONS: Our data demonstrate the cooperative effects of natriuretic peptide and DN-FOXO on promoting cardiomyocyte cell cycle activity and mouse cardiac repair and regeneration after injury.
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Ali et al. (2021) studied Myocardial Infarction. Atrial natriuretic peptide (ANP) and dominant-negative FOXO (DN-FOXO) vs. Ad-Cre (control) or single treatments was evaluated on Cardiomyocyte cell cycle activity (EdU+cTnT+ cells) and cardiac fibrosis area (p=<0.01). Combined treatment with atrial natriuretic peptide and dominant-negative FOXO cooperatively promoted cardiomyocyte cell cycle reactivation and reduced scar formation after myocardial infarction in neonatal mice.
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