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TRIM-containing 44 aggravates cardiac hypertrophy via TLR4/NOX4-induced ferroptosis

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Abstract

TRIM-containing 44 (TRIM44) is a promoter of multiple cancers. However, its role in cardiac hypertrophy has not been elucidated. This study explored the role of TRIM44 on pressure overload-induced cardiac hypertrophy in mice. Mice were subjected to aortic banding to establish an adverse cardiac hypertrophy model, followed by the administration of AAV9-TRIM44 or AAV9shTRIM44 to overexpress or knock down TRIM44. Echocardiography was used to assess cardiac function. H9c2 cells were cultured and transfected with either Ad-TRIM44 or TRIM44 siRNA to overexpress or silence TRIM44. Cells were also stimulated with angiotensin II to establish a cardiomyocyte hypertrophy model. Results indicated that TRIM44 was downregulated in mice hearts and cardiomyocytes that were treated with aortic banding or angiotensin II. TRIM44 overexpression in mice hearts aggravated cardiac hypertrophy and fibrosis, as well as inhibited cardiac function post-aortic banding. Moreover, mice with TRIM44 overexpression displayed increased ferroptosis post-aortic banding. Mice with TRIM44 knockdown revealed ameliorated cardiac hypertrophy, ferroptosis, and fibrosis, as well as improved cardiac function post-aortic banding. In H9c2 cells transfected with Ad-TRIM44, angiotensin II-induced ferroptosis was enhanced, while cells with silenced TRIM44 reported reduced ferroptosis post-angiotensin II administration. Furthermore, TRIM44 interacted with TLR4, which increased the expression of NOX4 and subsequently augmented ferroptosis-associated protein levels. By using TLR4 knockout mice, the inhibitory role of TRIM44 was reduced post-aortic banding. Taken together, TRIM44 aggravated pressure overload-induced cardiac hypertrophy via increased TLR4/NOX4-associated ferroptosis.

Key messages

  • TRIM44 could aggregate pressure overload-induced cardiac hypertrophy via increasing TLR4-NOX4 associated ferroptosis.

  • Target TRIM44 may become a new therapeutic method for preventing or treating pressure overload-induced cardiac hypertrophy.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This research was supported by the Henan Science and Technology Tackling Plan—Joint Construction Project [No. LHGJ20190100].

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Author notes

  1. Leiming Wu and Meng Jia contribute equally.

Authors and Affiliations

  1. Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, 450052, China

    Leiming Wu, Lili Xiao, Zheng Wang, Rui Yao, Yanzhou Zhang & Lu Gao

  2. Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Meng Jia

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  1. Leiming Wu
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  3. Lili Xiao
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  7. Lu Gao
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Contributions

Lu Gao and Yanzhou Zhang contributed to the conception and design of the experiments; Lu Gao, Leiming Wu, Lili Xiao, and Rui Yao carried out the experiments; Lili Xiao, Leiming Wu, and Zheng Wang analyzed the experimental results. Rui Yao wrote and revised the manuscript.

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Correspondence to Yanzhou Zhang or Lu Gao.

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Ethical approval

The animal experiments were performed according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996) and were approved by the Animal Care and Use Committee of the First Affiliated Hospital of Zhengzhou University (ZH-2021–0120).

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Wu, L., Jia, M., Xiao, L. et al. TRIM-containing 44 aggravates cardiac hypertrophy via TLR4/NOX4-induced ferroptosis. J Mol Med 101, 685–697 (2023). https://doi.org/10.1007/s00109-023-02318-3

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  • DOI: https://doi.org/10.1007/s00109-023-02318-3

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