Long-Acting Thioredoxin Ameliorates Doxorubicin-Induced Cardiomyopathy via Its Anti-Oxidative and Anti-Inflammatory Action.

Ryota Murata,Hiroshi Watanabe,Toru Maruyama,Hitoshi Maeda,Motohiro Nishida,Kento Nishida,Hiroto Nosaki

doi:10.3390/pharmaceutics14030562

Abstract

Although the number of patients with heart failure is increasing, a sufficient treatment agent has not been established. Oxidative stress and inflammation play important roles in the development of myocardial remodeling. When thioredoxin (Trx), an endogenous anti-oxidative and inflammatory modulator with a molecular weight of 12 kDa, is exogenously administered, it disappears rapidly from the blood circulation. In this study, we prepared a long-acting Trx, by fusing human Trx (HSA-Trx) with human serum albumin (HSA) and evaluated its efficacy in treating drug-induced heart failure. Drug-induced cardiomyopathy was created by intraperitoneally administering doxorubicin (Dox) to mice three times per week. A decrease in heart weight, increased myocardial fibrosis and markers for myocardial damage that were observed in the Dox group were suppressed by HSA-Trx administration. HSA-Trx also suppressed the expression of atrogin-1 and myostatin, myocardial atrophy factors in addition to suppressing oxidative stress and inflammation. In the Dox group, a decreased expression of endogenous Trx in cardiac tissue and an increased expression of macrophage migration inhibitory factor were observed, but these changes were restored to normal levels by HSA-Trx administration. These findings suggest that HSA-Trx improves the pathological condition associated with Dox-induced cardiomyopathy by its anti-oxidative/anti-inflammatory and myocardial atrophy inhibitory action.

Highlights

Introduction published maps and institutional affilHeart failure is caused by drug-induced cardiomyopathy, ischemic heart disease or hypertrophic cardiomyopathy
We evaluated the therapeutic effect of human serum albumin (HSA)-Trx on Dox-induced cardiomyopathy model mice (Figure S1)
It has been reported that the onset of Dox-induced cardiomyopathy is caused by oxidative stress produced by Dox itself [44], Shimauchi et al recently reported that Dox induces the expression of the Ca2+ transient receptor potential canonical (TRPC3), which is present in the myocardial cell membrane, and enhances reactive oxygen species (ROS) production from Nox2, resulting in the atrophy of cardiomyocytes [9]

Summary

Introduction

Heart failure is caused by drug-induced cardiomyopathy, ischemic heart disease or hypertrophic cardiomyopathy. The pathological condition progresses through morphological changes (myocardial remodeling) in the myocardium caused by the damage such as oxidative stress and inflammation [1]. Myocardial atrophic remodeling that has attracted attention in recent years is induced through the induction of myocardial atrophy factors such as the muscle-specific ubiquitin ligase atrogin-1 and myostatin [2]. The fibrosis that occurs during myocardial remodeling increases the risk of death in patients with heart failure [3]. Myocardial remodeling is an important therapeutic target for the treatment of heart failure pathology, an effective therapeutic agent for treating myocardial remodeling has not yet been developed. Oxidative stress and inflammatory response play a central role in the progression of myocardial remodeling. During the onset and progression of this pathology, an increase iations

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