Heat Shock Protein 22 Attenuates Doxorubicin-Induced Cardiotoxicity via Regulating Inflammation and Apoptosis.

Yin Lan,Yi Wang,Qiutang Zeng,Kun Huang

doi:10.3389/fphar.2020.00257

Abstract

BackgroundThe antitumor effect of doxorubicin (DOX) is limited by its acute and chronic toxicity to the heart, which causes heart injury. Heat shock protein 22 (Hsp22) is a protein proved to exert anti-apoptosis and anti-inflammatory effects in other diseases and physical conditions. In this study, we aim to explore whether Hsp22 could exert a protective role during cardiac injury in response to DOX.MethodsThe overexpression of Hsp22 was mediated via adenovirus vector to clarify the role of Hsp22 in the cardiac injury caused by DOX. DOX-induced acute heart injury mouse model was established by single intraperitoneal injection of DOX (15 mg/kg). Subsequently, cardiac staining and molecular biological analysis were performed to analyze the morphological and biochemical effects of Hsp22 on cardiac injury. H9c2 cells were used for validation in vitro.ResultsAn increase in the expression level of Hsp22 was observed in DOX-treated heart tissue. Furthermore, cardiac-specific overexpression of Hsp22 showed reduced cardiac dysfunction, decrease in inflammatory response, and reduction in cell apoptosis in injury heart and cardiomyocytes induced by DOX in vivo and in vitro. Moreover, the suppression of Toll-like receptor (TLR)4/NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) was associated with the protective effect of Hsp22. Finally, the protective effect of Hsp22 cardiac function was almost abolished by overexpression of NLRP3 in DOX-treated mice.ConclusionIn summary, Hsp22 overexpression in the heart could suppress cardiac injury in response to DOX treatment through blocking TLR4/NLRP3 activation. Hsp22 may become a new therapeutic method for treating cardiac injury induced by DOX in cancer patients.

Highlights

Doxorubicin (DOX) is a highly effective chemotherapy drug used to treat tumors, including solid and hematopoietic tumors
Consistent with the previous studies, our present study found that Heat shock protein 22 (Hsp22) protein level was decreased after DOX treatment in C57BL/6 mice; there is some potential for Hsp22 to be a defender in the treatment of DOXinduced cardiomyopathy
Our results show that Hsp22 can reduce the activation of Nuclear factor (NF)-kB in cardiomyocytes and its nuclear translocation in cardiomyocytes of C57BL/6 mice, thereby diminishing the synthesis and release of pro-inflammatory factors, which might reduce the inflammatory response of the cardiomyocytes

Summary

Introduction

Doxorubicin (DOX) is a highly effective chemotherapy drug used to treat tumors, including solid and hematopoietic tumors. Doxorubicin-related cardiotoxicity is a common adverse drug reaction, which includes severe arrhythmia, myocardial infarction, and left ventricular dysfunction. The incidence of adverse drug reaction is approximately 30%–40% of the patients who received DOX treatment (Ferreira et al, 2008). The probability of developing congestive heart failure after doxorubicin treatment is estimated to be 1%–2%, which is significantly associated with high mortality in cancer chemotherapy patients (Yeh and Bickford, 2009; Plummer et al, 2019). There is no specific treatment for heart injury induced by DOX. It is urgent to find new ways to treat DOX-induced heart injury. The antitumor effect of doxorubicin (DOX) is limited by its acute and chronic toxicity to the heart, which causes heart injury.

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