Cardiomyocyte S1PR1 promotes cardiac regeneration via AKT/mTORC1 signaling pathway

<b>Aims:</b> Lower vertebrates and some neonatal mammals are known to possess the ability to regenerate cardiomyocyte and fully recover after heart injuries within a limited period. Understanding the molecular mechanisms of heart regeneration and exploring new ways to enhance cardiac regeneration hold significant promise for therapeutic intervention of heart failure. Sphingosine 1-phospahte receptor 1 (S1PR1) is highly expressed in cardiomyocytes and plays a crucial role in heart development and pathological cardiac remodeling. However, the effect of cardiomyocyte-expressing S1PR1 on heart regeneration has not yet been elucidated. This study aims to investigate the role of cardiomyocyte S1PR1 in cardiac regeneration following heart injuries. <b>Methods and Results:</b> We generated cardiomyocyte (CM)-specific <i>S1pr1</i> knock-out mice and demonstrated that CM-specific <i>S1pr1</i> loss-of-function severely reduced cardiomyocyte proliferation and inhibited heart regeneration following apex resection in neonatal mice. Conversely, AAV9-mediated CM-specific <i>S1pr1</i> gain-of-function significantly enhanced cardiac regeneration. We identified that S1PR1 activated the AKT/mTORC1/CYCLIN D1 and BCL2 signaling pathways to promote cardiomyocyte proliferation and inhibit apoptosis. Moreover, CM-targeted gene delivery system via AAV9 to overexpress S1PR1 significantly increased cardiomyocyte proliferation and improved cardiac functions following myocardial infarction in adult mice, suggesting a potential method to enhance cardiac regeneration and improve cardiac function in the injured heart. <b>Conclusions:</b> This study demonstrates that CM-S1PR1 plays an essential role in cardiomyocyte proliferation and heart regeneration. This research provides a potential strategy by CM-targeted S1PR1 overexpression as a new therapeutic intervention for heart failure.