Abstract
Background. Previous research has shown that peroxiredoxin 1 (Prdx1) is an important modulator of physiological and pathophysiological cardiovascular events. This study is aimed at investigating the role and underlying mechanism of Prdx1 in doxorubicin- (DOX-) induced cardiotoxicity. Cardiac-specific expression of Prdx1 was induced in mice, and the mice received a single dose of DOX (15 mg/kg) to generate cardiotoxicity. First, our study demonstrated that Prdx1 expression was upregulated in the heart and in cardiomyocytes after DOX treatment. Second, we provided direct evidence that Prdx1 overexpression ameliorated DOX-induced cardiotoxicity by attenuating oxidative stress and cardiomyocyte apoptosis. Mechanistically, we found that DOX treatment increased the phosphorylation level of apoptosis signal-regulating kinase-1 (ASK1) and the downstream protein p38 in the heart and in cardiomyocytes, and these effects were decreased by Prdx1 overexpression. In contrast, inhibiting Prdx1 promoted DOX-induced cardiac injury via the ASK1/p38 pathway. These results suggest that Prdx1 may be an effective therapeutic option to prevent DOX-induced cardiotoxicity.
Highlights
Doxorubicin (DOX), an anthracycline antibiotic, is a broadspectrum antitumor drug that is widely used in the clinical treatment of various malignant tumors [1, 2]
peroxiredoxin 1 (Prdx1) Expression Is Increased in the Heart and in Cardiomyocytes after DOX Treatment
Western blotting and RT-PCR analyses showed that Prdx1 mRNA and protein expressions were increased in the heart 8 days after DOX treatment (Figure 1(a))
Summary
Doxorubicin (DOX), an anthracycline antibiotic, is a broadspectrum antitumor drug that is widely used in the clinical treatment of various malignant tumors [1, 2]. Multiple molecular mechanisms have been reported to contribute to the processes of DOX-induced myocardial injury, including oxidative stress, the inflammatory response, mitochondrial dysfunction, and cardiomyocyte apoptosis [7, 8]. Our study demonstrated that Prdx expression was upregulated in the heart and in cardiomyocytes after DOX treatment. We provided direct evidence that Prdx overexpression ameliorated DOX-induced cardiotoxicity by attenuating oxidative stress and cardiomyocyte apoptosis. We found that DOX treatment increased the phosphorylation level of apoptosis signal-regulating kinase-1 (ASK1) and the downstream protein p38 in the heart and in cardiomyocytes, and these effects were decreased by Prdx overexpression. Inhibiting Prdx promoted DOX-induced cardiac injury via the ASK1/p38 pathway. These results suggest that Prdx may be an effective therapeutic option to prevent DOX-induced cardiotoxicity
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