Stimulation of Sigma-1 Receptor Protects against Cardiac Fibrosis by Alleviating IRE1 Pathway and Autophagy Impairment.

Jing Qu,Junli Li,Dongxu Li,Wenchao Wu,Yanguo Xin,Xiaojing Liu,Song Lei,Miaoling Li,Maria C Albertini

doi:10.1155/2021/8836818

Abstract

Sigma-1 receptor (Sig1R), a chaperone in the endoplasmic reticulum (ER) membrane, has been implicated in cardiac hypertrophy; however, its role in cardiac fibroblast activation has not been established. This study investigated the possible association between Sig1R and this activation by subjecting mice to sham, transverse aortic constriction (TAC), and TAC plus fluvoxamine (an agonist of Sig1R) treatments. Cardiac function and fibrosis were evaluated four weeks later by echocardiography and histological staining. In an in vitro study, neonatal rat cardiac fibroblasts were treated with fluvoxamine or NE-100 (an antagonist of Sig1R) in the presence or absence of transforming growth factor beta1 (TGF-β1). Fibrotic markers, ER stress pathways, and autophagy were then investigated by qPCR, western blotting, immunofluorescence, confocal microscopy, and transmission electron microscopy. Fluvoxamine treatment reduced cardiac fibrosis, preserved cardiac function, and attenuated cardiac fibroblast activation. Inhibition of the IRE1/XBP1 pathway, a branch of ER stress, by a specific inhibitor of IRE1 endonuclease activity, attenuated the pathological process. Fluvoxamine stimulation of Sig1R restored autophagic flux in cardiac fibroblasts, indicating that Sig1R appears to play a protective role in the activation of cardiac fibroblasts by inhibiting the IRE1 pathway and restoring autophagic flux. Sig1R may therefore represent a therapeutic target for cardiac fibrosis.

Highlights

Cardiac fibrosis is characterized by the cardiac fibroblast activation, excessive proliferation, and transition into myofibroblast, which lead to excessive deposition and abnormal distribution of extracellular matrix [1,2,3]
Cardiac function of transverse aortic constriction (TAC) mice was significantly decreased as shown by lower fractional shortening (FS), ejection fraction (EF), diastolic interventricular septum (IVS), and left ventricular posterior wall (LVPW) thickness (Figure 1(b))
The protein expressions of POSTN, α-SMA, connective tissue growth factor (CTGF), and transforming growth factor-β (TGF-β) were increased by 5.6, 2.5, 2.4, and 2.2-fold, respectively, in the TAC group compared with the Sham group (Figures 1(k) and 1(l))

Summary

Introduction

Cardiac fibrosis is characterized by the cardiac fibroblast activation, excessive proliferation, and transition into myofibroblast, which lead to excessive deposition and abnormal distribution of extracellular matrix [1,2,3]. It is known that various cellular signaling pathways, such as the renin-angiotensin system, inflammatory factors, and oxidative stress are involved in the process of cardiac fibrosis, whereas the underling mechanisms, especially myocardial fibroblast activation, is not fully understood [7, 8]. Fluvoxamine, a selective serotonin reuptake inhibitor with high affinity for the Sig1R, ameliorates cardiac hypertrophy and dysfunction deriving from Sig1R activation [26,27,28,29]. While this finding introduces the role of Sig1R in modulating cardiovascular disease, it raises many questions regarding the underline mechanisms, especially in cardiac fibrosis. In this study, we determined how Sig1R regulates cardiac fibrosis and cardiac fibroblasts activation, as well as its roles in ER stress, autophagy

Methods and Materials

Results

Discussion

Conflicts of Interest