Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway
Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway
复制标题
内皮 S1pr1 通过 AKT-eNOS 通路调节压力超负荷诱导的心脏重塑
DOI：
10.1111/jcmm.14900
复制
发表时间：
2019-12-19
影响因子：
5.3
通讯作者：
Zhang, Lin
中科院分区：
文献类型：
--
作者：
Liu, Xiuxiang;Wu, Jinjin;Zhang, Lin
心脏血管微环境在心力衰竭过程中对心脏重构起着至关重要的作用。1-磷酸鞘氨醇(S1P)通过其受体S1PR1严格调节血管内环境的稳定。因此，我们推测内皮细胞S1PR1可能参与了病理性心脏重构。本研究采用横行主动脉缩窄(TAC)手术建立心力衰竭模型。TAC术后心脏微血管内皮细胞(ECs)中S1PR1表达显著增加。内皮特异性S1PR1基因缺失显著加重心功能障碍，加重心肌肥大和纤维化。体外实验证明，S1P/S1PR1激活了AKT/eNOS信号通路，导致一氧化氮(NO)的产生增加，这是一种重要的心脏保护因子。抑制AKT/eNOS通路可逆转EC-S1PR1过表达对血管紧张素II(AngII)诱导的心肌细胞肥大的抑制作用以及对转化生长因子-β介导的心肌成纤维细胞增殖和向成肌细胞转化的抑制作用。最后，S1PR1的药理激活改善了TAC诱导的心肌肥大和纤维化，导致心功能的改善。综上所述，我们的结果提示EC-S1PR1可能通过AKT/eNOS途径预防压力超负荷所致心力衰竭的发展，因此药物激活S1PR1或EC靶向的S1PR1-AKT-eNOS通路可能为改善心力衰竭过程中的心功能提供一种新的治疗方法。
Cardiac vascular microenvironment is crucial for cardiac remodelling during the process of heart failure. Sphingosine 1-phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post-TAC hearts. Endothelial-specific deletion of S1pr1 significantly aggravated cardiac dysfunction and deteriorated cardiac hypertrophy and fibrosis in myocardium. In vitro experiments demonstrated that S1P/S1pr1 praxis activated AKT/eNOS signalling pathway, leading to more production of nitric oxide (NO), which is an essential cardiac protective factor. Inhibition of AKT/eNOS pathway reversed the inhibitory effect of EC-S1pr1-overexpression on angiotensin II (AngII)-induced cardiomyocyte (CM) hypertrophy, as well as on TGF-beta-mediated cardiac fibroblast proliferation and transformation towards myofibroblasts. Finally, pharmacological activation of S1pr1 ameliorated TAC-induced cardiac hypertrophy and fibrosis, leading to an improvement in cardiac function. Together, our results suggest that EC-S1pr1 might prevent the development of pressure overload-induced heart failure via AKT/eNOS pathway, and thus pharmacological activation of S1pr1 or EC-targeting S1pr1-AKT-eNOS pathway could provide a future novel therapy to improve cardiac function during heart failure development.