Objective:To explore whether and how the knockdown of Popdc2 with siRNA produced changes in the proliferative activity of neonatal rat cardiomyocytes. Methods:Postnatal of 0,7,14 day of Sprague Dawley rats cardiac tissue was prepared,qRT-PCR was performed to detect the Popdc2 relative mRNA expression level. Neonatal rat cardiomyocytes and fibroblast were prepared from the ventricles of Sprague Dawley rats aged 0~2 days,qRT-PCR was performed to detected Popdc family member mRNA expression level in cardiomyocytes and Popdc2 mRNA expression level in cardiomyocytes and fibroblast;negative control(NC)and Popdc2 small interference RNAs (si-Popdc2) were transferred into neonatal rat cardiomyocytes,EdU incorporation assay and Ki67 staining were used to detect cell proliferation,qRT-PCR was performed to detect the Popdc2,TBX20,TBX5,and Ki67 relative mRNA expression level,Western blot was used to test the total Akt and phosphorylation Akt protein expression level. Results:This study showed that Popdc2 mRNA expression level was the highest of Popdc family member in cardiomyocytes (P < 0.01). The expression was continuely increased after postnatal(P < 0.01),Popdc2 mRNA expression level was higher in cardiomyocytes compared with fibroblast(P < 0.05);EdU incorporation assay showed that knockdown of Popdc2 promoted cardiomyocytes DNA systhesis(P < 0.05),immune staining showed knockdown of Popdc2 increased the Ki67 position cardiomyocytes number (P < 0.05),qRT-PCR showed that knockdown of Popdc2 upregulated transcription factor TBX20(P < 0.01),TBX5(P < 0.05)),and proliferation protein Ki67(P < 0.05)mRNA expression level,Western blot showed that knockdown of Popdc2 significantly increased phosphorylation of Akt protein level,Akt308 (P < 0.05),Akt473 (P < 0.001). Conclusion:The present study demonstrated that knockdown of Popdc2 produced a significant increase in the proliferation of neonatal cardiomyocytes,and may via Akt phosphorylation and regulate cardiac transcription factor,suggesting that Popdc2 may become a therapeutic target for cardiac repair and heart regeneration.