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HMOX1 silencing prevents doxorubicin-induced cardiomyocyte injury, mitochondrial dysfunction, and ferroptosis by downregulating CTGF

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Abstract

Objectives

Doxorubicin is a type of effective antitumor drug but can contribute to cardiomyocyte injuries. We aimed to dissect the mechanism of the HMOX1/CTGF axis in DOX-induced cardiomyocyte injury, mitochondrial dysfunction, and ferroptosis.

Methods

Bioinformatics analysis was conducted to retrieve differentially expressed genes in a DOX-induced mouse model. Mouse cardiomyocytes, HL-1 cells, were induced with l µM DOX, after which gain- or loss-of-function assays were applied. CCK-8, fluorescent probe assay, flow cytometry, and corresponding kits were employed to detect cell viability, ROS levels, mitochondrial membrane potential and cell apoptosis, and GSH and Fe2+ contents, respectively. qRT-PCR or Western blot assay was adopted to test HMOX1, CTGF, BCL-2, Caspase3, Cleaved-Caspase3, and GPX4 expression.

Results

Bioinformatics analysis showed that HMOX1 and CTGF were highly expressed in DOX-induced mice and correlated with each other. Also, HMOX1 and CTGF expression was high in HL-1 cells after DOX treatment, along with an obvious decrease in cell viability and GSH and GPX4 expression, an increase in ROS levels, apoptosis, and Fe2+ contents, and mitochondrial membrane potential dysfunction or loss. HMOX1 or CTGF silencing diminished cell apoptosis, Cleaved-Caspase3 expression, Fe2+ contents, and ROS levels, enhanced cell viability and the expression of GSH, GPX4, and BCL-2, and recovered mitochondrial membrane potential in DOX-induced HL-1 cells. Nevertheless, the effects of HMOX1 silencing on the viability, apoptosis, ferroptosis, and mitochondrial dysfunction of DOX-induced HL-1 cells were counteracted by CTGF overexpression.

Conclusions

In conclusion, HMOX1 silencing decreased CTGF expression to alleviate DOX-induced injury, mitochondrial dysfunction, and ferroptosis of mouse cardiomyocytes.

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Authors and Affiliations

  1. Department of Heart Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 110, Ganhe Road, Hongkou District, Shanghai, 200437, People’s Republic of China

    Jia Qian, Wenting Wan & Min Fan

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Qian, J., Wan, W. & Fan, M. HMOX1 silencing prevents doxorubicin-induced cardiomyocyte injury, mitochondrial dysfunction, and ferroptosis by downregulating CTGF. Gen Thorac Cardiovasc Surg 71, 280–290 (2023). https://doi.org/10.1007/s11748-022-01867-7

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