Sigma-1 Receptor Activation Attenuates DOX-induced Cardiotoxicity by Alleviating Endoplasmic Reticulum Stress and Mitochondrial Calcium Overload Via PERK and IP3R-VDAC1-MCU Signaling Pathways

Overview

Journal Biol Direct

Publisher Biomed Central

Specialty Biology

Date 2025 Feb 26

PMID 40001213

Authors

Zixuan Li

Qian Ran

Chuan Qu

Shan Hu

Shengyu Cui

You Zhou

Bo Shen

Bo Yang

Affiliations

Soon will be listed here.

Abstract

Background: Doxorubicin (DOX) is an anthracycline with potent antitumor properties and rare yet serious cardiotoxic side effects that limit its clinical application. The sigma-1 receptor is a stress-triggered chaperone often dysregulated in diseases and has known cardioprotective effects. Although its anti-oxidative stress and anti-apoptotic effects have been demonstrated, its effectiveness in DOX-induced cardiotoxicity has never been explored. This study investigated the potential role of the activated sigma-1 receptor in a DOX-induced murine cardiotoxicity model to elucidate the receptor's mechanism of action.

Methods: We established the model in C57BL/6 mice by daily intraperitoneal injections of fluvoxamine (Flv) for 4 consecutive weeks to activate the receptor and by weekly intraperitoneal injections of DOX at 5 mg/kg for 3 weeks. We performed in vitro experiments using cardiomyocytes of neonatal Sprague-Dawley rats to verify the protective effect of the sigma-1 receptor.

Results: We found that sigma-1 expression in the heart decreased in the DOX-treated mice, and activating the receptor with Flv improved cardiac function. Moreover, Flv pretreatment inhibited cardiomyocyte apoptosis and endoplasmic reticulum stress and increased the expression of the Bcl2 apoptosis regulator (Bcl2), effectively alleviating the pathophysiological manifestations in mice. In addition, activating the receptor exerted cardioprotective effects by modulating endoplasmic reticulum stress through the PRKR-like endoplasmic reticulum kinase (PERK) signaling pathway. It also reduced mitochondrial and endoplasmic reticulum contact and alleviated mitochondrial calcium overload through the IP3R-VDAC1-MCU signaling pathway.

Conclusion: In conclusion, our study emphasizes the therapeutic potential of activating sigma-1 receptors against DOX-induced cardiotoxicity, suggesting sigma-1 receptors as potential therapeutic targets for this disease.

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