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. 2020 Jul 29:2020:2405135.
doi: 10.1155/2020/2405135. eCollection 2020.

Peroxiredoxin-1 Overexpression Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Oxidative Stress and Cardiomyocyte Apoptosis

Lai Jiang  1 , Yanping Gong  1 , Yida Hu  2 , Yangyang You  3 , Jiawu Wang  4 , Zhetao Zhang  5 , Zeyuan Wei  5 , Chaoliang Tang  4
Affiliations

Peroxiredoxin-1 Overexpression Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Oxidative Stress and Cardiomyocyte Apoptosis

Lai Jiang et al. Oxid Med Cell Longev. .

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.

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Conflict of interest statement

No conflicts of interest are declared by the authors.

Figures

Figure 1
Figure 1
Prdx1 expression is increased in the heart and in cardiomyocytes after DOX treatment. (a) The protein and mRNA expression of Prdx1 in the heart 8 days after DOX treatment (n = 4, ∗P < 0.05 compared with the NS group). (b) The protein and mRNA expression of Prdx1 in cardiomyocytes treated with DOX (n = 4, ∗P < 0.05 compared with the PBS group).
Figure 2
Figure 2
Prdx1 overexpression protected against cardiac injury induced by DOX. (a) The protein levels of Prdx1 four weeks after AAV9-Prdx1 injection in mice (n = 4). (b, c) The results of body weight and HW/TL ratio measurements in mice (n = 6). (d–g) Biochemical determination of CK-MB and LDH levels in the heart and serum for the indicated groups (n = 6). (h) HE staining shows the pathological structure of the heart in mice (n = 5). ∗P < 0.05 compared with the NS group; #P < 0.05 compared with the DOX group.
Figure 3
Figure 3
Prdx1 overexpression attenuated cardiac dysfunction induced by DOX. (a, b) Echocardiographic parameters for each group (n = 8). (c–g) Hemodynamic parameters for each group (n = 6). ∗P < 0.05 compared with the NS group; #P < 0.05 compared with the DOX group.
Figure 4
Figure 4
Prdx1 overexpression attenuated oxidative stress induced by DOX. (a–d) Quantitative results for SOD, CAT, NADPH oxidase activity, and MDA content in the hearts of mice (n = 6). (e) Representative DHE staining images of the heart (n = 5). ∗P < 0.05 compared with the NS group; #P < 0.05 compared with the DOX group.
Figure 5
Figure 5
Prdx1 overexpression attenuated cardiomyocyte apoptosis induced by DOX. (a) Western blots showing the Bcl-2, Bax, and c-caspase3 levels in the hearts of mice (n = 4). (b) Representative TUNEL staining images of the heart (n = 5). ∗P < 0.05 compared with the NS group; #P < 0.05 compared with the DOX group.
Figure 6
Figure 6
Prdx1 overexpression relieves DOX-induced cardiotoxicity in vitro. (a–d) Quantitative results for SOD, CAT, NADPH oxidase activity, and MDA content in each group (n = 6). (e) Western blots showing the Bcl-2, Bax, and c-caspase3 levels in each group (n = 4). ∗P < 0.05 compared with the PBS group; #P < 0.05 compared with the DOX group.
Figure 7
Figure 7
Prdx1 overexpression inhibits ASK1/p38 pathway activation. (a) Western blots showing the p-ASK1, ASK1, p-p38, and p38 levels in the hearts of mice (n = 4). (b) Western blots showing the p-ASK1, ASK1, p-p38, and p38 levels in NVRMs (n = 4). ∗P < 0.05 compared with the NS or PBS group; #P < 0.05 compared with the DOX group.
Figure 8
Figure 8
Prdx1 inhibition exacerbated DOX-induced cardiotoxicity. (a–d) Quantitative results for SOD, CAT, NADPH oxidase activity, and MDA content in each group (n = 6). (e) Western blots showing the Bcl-2, Bax, and c-caspase3 levels in each group (n = 4). ∗P < 0.05 compared with the PBS+Ad-NC group; #P < 0.05 compared with the DOX+Ad-NC group; &P < 0.05 compared with the DOX+Ad-Prdx1 group.
Figure 9
Figure 9
Peroxiredoxin-1 overexpression attenuates doxorubicin-induced cardiotoxicity by inhibiting oxidative stress and cardiomyocyte apoptosis.
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