Activation of Nrf2 by miR‐152 Inhibits Doxorubicin‐Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis

Wenbin Zhang; Xin Lai; Xufeng Guo

doi:10.1155/2021/8860883

January 1, 2021Oxidative Medicine and Cellular LongevityOpen Access

Activation of Nrf2 by miR‐152 Inhibits Doxorubicin‐Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis

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Why the study?

Doxorubicin can trigger congestive heart failure, and microRNAs are involved in the pathogenesis of doxorubicin-induced cardiomyopathy, but the effect of miR-152 remained to be investigated.

Does miR-152 overexpression prevent doxorubicin-induced cardiotoxicity in mice?

Structured PICO

Does miR-152 overexpression prevent doxorubicin-induced cardiotoxicity in mice?

P

Population

Mice and cardiomyocytes treated with doxorubicin (DOX)

I

Intervention

Overexpression of miR-152 using an adeno-associated viral vector 6 weeks before DOX treatment

C

Comparator

Control mice/cardiomyocytes treated with DOX (and miR-152 knockdown models)

O

Outcome

DOX-induced cardiotoxicity (cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis)surrogate

miR-152 protects against doxorubicin-induced cardiotoxicity in mice by activating the Nrf2 signaling pathway, suggesting a potential therapeutic target.

Implication

Hypothesis-generating for miR-152/Nrf2 in doxorubicin cardiotoxicity; clinical translation requires prospective human studies.

Abstract

Doxorubicin (DOX) could trigger congestive heart failure, which largely limited the clinical use of DOX. microRNAs (miRNAs) were closely involved in the pathogenesis of DOX-induced cardiomyopathy. Here, we aimed to investigate the effect of miR-152 on DOX-induced cardiotoxicity in mice. To study this, we used an adeno-associated viral vector to overexpress miR-152 in mice 6 weeks before DOX treatment, using a dose mimicking the concentrations used in the clinics. In response to DOX injection, miR-152 was significantly decreased in murine hearts and cardiomyocytes. After DOX treatment, mice with miR-152 overexpression in the hearts developed less cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis. Furthermore, we found that miR-152 overexpression attenuated DOX-related oxidative stress, inflammation, and cell loss in cardiomyocytes, whereas miR-152 knockdown resulted in oxidative stress, inflammation, and cell loss in cardiomyocytes. Mechanistically, this effect of miR-152 was dependent on the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in response to DOX. Notably, Nrf2 deficiency blocked the protective effects of miR-152 against DOX-related cardiac injury in mice. In conclusion, miR-152 protected against DOX-induced cardiotoxicity via the activation of the Nrf2 signaling pathway. These results suggest that miR-152 may be a promising therapeutic target for the treatment of DOX-induced cardiotoxicity.