Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway.

Xiuxiang Liu,Jinjin Wu,Yuzhen Zhang,Yashu Kuang,Huimin Fan,Jie Liu,Hao Hu,Chenying Zhu,Yanfang Wang,Xiaoli Chen,Tao Zhuang,Lin Zhang,Zhongmin Liu,Ping Yu

doi:10.1111/jcmm.14900

Abstract

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‐β‐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.

Highlights

Heart failure is a leading cause of morbidity and mortality worldwide.[1]
Immunostaining of Wheat Germ Agglutinin (WGA), which binds to glycoprotein of the cell membrane, showed that loss of endothelial cells (ECs)-S1pr[1] significantly increased cardiomyocyte cross-sectional area in the mice following transverse aortic constriction (TAC) operation (Figure 2D), while cardiac microvessel density was not altered in S1pr1ECKO mice as shown by isolectin-B4 staining in banded hearts (Figure 2E)
It was well known that the foetal gene program was reactivated in the pathophysiological process of cardiac hypertrophy,[3] we investigated the influences of EC-S1pr[1] on the expression of foetal genes in cardiomyocytes

Summary

| INTRODUCTION

Heart failure is a leading cause of morbidity and mortality worldwide.[1]. Cardiac hypertrophy develops as a compensatory response of the heart towards haemodynamic overload, such as hypertension and valvular heart disease.[1]. It has been known that sphingosine 1-phosphate receptor 1 (S1pr1) was highly expressed in vascular endothelial cells and played a vital role in endothelial functions.[6,7] Previous studies have shown that EC-S1pr[1] tightly controlled the integrity of endothelium by stabilization of VE-cadherin at endothelial junctions.[8] Loss of S1pr[1] or pharmacological blockade of S1pr[1] resulted in increased permeability of blood vessels.[6] Deletion of S1pr[1] gene in mice caused embryonic death at E12.5-14.5 due to a severe defect in vasculature development.[6] Given that EC-S1pr[1] plays an important role in the control of vascular homeostasis and that cardiac ECs exert an active player in cardiac physiology and pathology, we hypothesized that EC-S1pr[1] might influence cardiac remodelling during pressure overload-induced heart failure. Pharmacological activation of S1pr[1] significantly ameliorated pressure overload-induced cardiac hypertrophy and fibrosis, and improved cardiac function in vivo, suggesting that EC-S1pr[1] signals as a potential target to therapy heart failure

| MATERIALS AND METHODS

| DISCUSSION