Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
BMC Dev Biol. 2021 Feb 3;21(1):6. doi: 10.1186/s12861-020-00236-y.
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.
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.
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.
心肌细胞在胎儿期快速增殖，但出生后不久便失去增殖能力。然而，在细胞周期终末退出之前，心肌细胞在小鼠出生后早期经历另一个细胞周期。虽然在新生鼠心脏中观察到心肌细胞中 DNA 合成的短暂增加，但描述心肌细胞细胞周期再进入的分子机制仍知之甚少。心房利钠肽（ANP）和脑利钠肽（BNP）在胚胎心脏心室中大量表达。出生后，两种基因在心室心肌中的表达均强烈降低。叉头框 O（FOXO）转录因子在胚胎和出生后心脏心室中均有表达。它们的转录活性负性影响心肌细胞增殖。磷酸化后，FOXO 易位到细胞质中，转录失活。尽管有这些重要发现，但ANP 和 FOXO 是否协同作用于调节出生后早期心肌细胞细胞周期活性仍知之甚少。
我们观察到，在新生鼠心脏心室中，ANP 和 BNP 的表达和磷酸化 FOXO 的水平短暂增加，这与小鼠出生后早期心肌细胞细胞周期再进入的爆发相吻合。细胞培养研究表明，ANP/BNP 信号和 FOXO 协同促进新生鼠心肌细胞的细胞周期活性。在 ANP/BNP 和显性失活 FOXO（DN-FOXO）联合处理中观察到的增强的细胞周期活性，DN-FOXO 可以结合 DNA 上的 FOXO 识别位点，但不能激活转录，主要是通过利钠肽受体 3（Npr3）介导的。在小鼠中，在出生后心脏中同时应用 ANP 和 DN-FOXO 可使心肌细胞中的细胞周期重新激活，导致实验性心肌梗死后瘢痕形成减少。
我们的数据表明，利钠肽和 DN-FOXO 对促进心肌细胞细胞周期活性以及损伤后小鼠心脏修复和再生具有协同作用。
