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Atorvastatin-induced tolerogenic dendritic cells improve cardiac remodeling by suppressing TLR-4/NF-κB activation after myocardial infarction

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Abstract

Objective

Myocardial infarction (MI) caused by ischemic cardiomyocyte necrosis induces inflammatory responses that strongly affect ventricular remodeling. Tolerogenic dendritic cells (tDCs) can suppress this effect on inflammatory responses. However, the precise role of atorvastatin-induced tDCs in ventricular remodeling after MI remains unclear.

Methods

To explore the effect of necrotic cardiomyocytes (SNC) and/or atorvastatin on DC function, the expression of CD40, CD80, CD86, and MHC-II was determined using flow cytometry. The protein levels of TLR-4/NF-κB-related molecules were evaluated using western blotting. The infarct area after MI was determined via 2,3,5-triphenyltetrazolium chloride staining. The TUNEL assay was employed to evaluate the apoptosis of cardiomyocytes in heart sections. Masson’s trichrome method was used to determine the extent of fibrosis.

Results

Compared to the DCs co-cultured with PBS (control), cells co-cultured with Supernatant-IM or Supernatant-NH produced higher levels of inflammatory cytokines, including TNF-α, IL-1, IL-6, IL-12P40, and IL-8. This cytokine production was impaired by atorvastatin treatment. SNC treatment induced DC maturation and enhanced inflammatory cytokine secretion and oxidative stress through TLR-4/NF-κB pathway activation. Compared to that in the PBS-treated group, the left ventricular ejection fraction was significantly improved after tDC treatment. Additionally, compared to that in the PBS-treated group, tDC treatment reduced the left ventricular end-diastolic and end-systolic diameters in mice. Furthermore, treatment with tDCs improved the left ventricular systolic function, attenuated inflammatory cell infiltration, and reduced cardiomyocyte apoptosis, myocardial fibrosis, and infarct size compared to those in the control group.

Conclusions

Adoptive transfer of atorvastatin-induced tDCs alleviated post-infarction cardiomyocyte apoptosis and myocardial fibrosis in association with decreased inflammatory cell infiltration and inhibited oxidative stress, likely by suppressing TLR-4/NF-κB activation after myocardial infarction.

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Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

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Acknowledgements

This study was supported by the Natural Science Foundation of Jiangxi Province (Grant Nos. 20192ACBL21040 and 20204BCJ23017), National Natural Science Foundation of China (Grant Nos. 81800324, 81960061), and Qingdao Outstanding Health Professional Development Fund. A preprint has previously been published [39].

Author information

Author notes

  1. Qian Wang, Zhaoyang Chen, and Junjie Guo have contributed equally to this work.

Authors and Affiliations

  1. Department of Blood Transfusion, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, People’s Republic of China

    Qian Wang

  2. Heart Center of Fujian Province, Union Hospital, Fujian Medical University, 29 Xin-Quan Road, Fuzhou, 350001, People’s Republic of China

    Zhaoyang Chen & Hang Chen

  3. Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China

    Junjie Guo

  4. Qingdao Municipal Key Laboratory of Hypertension, Qingdao, Shandong, People’s Republic of China

    Junjie Guo

  5. Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, People’s Republic of China

    Xiaoping Peng, Zeqi Zheng & Jianbing Zhu

  6. Jiangxi Hypertension Research Institute, Nanchang, People’s Republic of China

    Xiaoping Peng, Zeqi Zheng & Jianbing Zhu

  7. Department of Cardiology, Qingpu Branch of Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of China

    Haibo Liu

  8. Department of Cardiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of China

    Yuanji Ma

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Contributions

QW, ZC, and JG performed the experiments and wrote the manuscript. XP and ZZ supervised the study and revised the manuscript. HL, YM and HC analyzed the data. JZ designed the experiment. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jianbing Zhu.

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Conflict of interest

The authors declare that there are no conflicts of interest.

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All authors have approved the manuscript and have agreed to submit to your journal. This manuscript has not been published or presented elsewhere, in part or in its entirety, and is not under consideration by another journal.

Ethics approval and consent to participate

The study design was approved by the ethics committee of The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province. All procedures performed in studies involving animals were in accordance with the ethical standards of the Laboratory Animal Management and Experimental Ethics Committee of The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province. All methods were performed in accordance with relevant guidelines and regulations.

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Wang, Q., Chen, Z., Guo, J. et al. Atorvastatin-induced tolerogenic dendritic cells improve cardiac remodeling by suppressing TLR-4/NF-κB activation after myocardial infarction. Inflamm. Res. 72, 13–25 (2023). https://doi.org/10.1007/s00011-022-01654-3

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  • DOI: https://doi.org/10.1007/s00011-022-01654-3

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