Cardiomyocyte S1PR1 Promotes Cardiac Regeneration Via AKT/mTORC1 Signaling Pathway

Overview

Journal Theranostics

Date 2025 Jan 16

PMID 39816679

Authors

Xiuxiang Liu

Jinnan Yue

Caixia Zhou

Yunhao Duan

Xiaoli Chen

Jie Liu

Shougang Zhuang

Yu Luo

Jinjin Wu

Yuzhen Zhang

Lin Zhang

Affiliations

Soon will be listed here.

Abstract

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. We generated cardiomyocyte (CM)-specific knock-out mice and demonstrated that CM-specific loss-of-function severely reduced cardiomyocyte proliferation and inhibited heart regeneration following apex resection in neonatal mice. Conversely, AAV9-mediated CM-specific 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. 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.

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