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Protective effects of 4-methylumbelliferone on myocardial ischemia/reperfusion injury in rats through inhibition of oxidative stress and downregulation of TLR4/NF-κB/NLRP3 signaling pathway

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Abstract

Myocardial ischemia–reperfusion injury (MI/R) has been found to be one of the important risk factors for global cardiac mortality and morbidity. The study was conducted to inquire into the protective effect of 4-methylumbilliferon (4-MU) against MI/R in rats and clarify its potential underlying mechanism. Animals were divided into four groups (n = 15) including sham, MI/R, MI/R + vehicle, and MI/R + 4-MU. MI/R was established in Wistar rats by occluding the left anterior descending (LAD) coronary artery for 30 min. 4-MU (25 mg/kg) was injected intraperitoneally before the induction of reperfusion. Cardiac function, fibrosis, oxidant/antioxidant markers, and inflammatory cytokines were evaluated using echocardiography, ELISA, and Western blot assay. As a result of MI/R induction, a decrease in left ventricular contractile function occurred along with increased cardiac fibrosis and tissue damage. The serum levels of TNF-α, IL-1β, and IL-18 increased, while IL-10 decreased. Oxidant/antioxidant changes were evident with increased MDA levels and decreased GSH, SOD, and CAT in the MI/R group. Furthermore, the protein levels of TLR4, NF-κB, and NLRP3 were significantly increased in the heart tissue of MI/R group. Treatment with 4-MU significantly prevented the reduction of cardiac contractile function and its pathological changes as a result of MI/R by inhibiting the increase of serum inflammatory factors and improving the oxidant/antioxidant balance probably through the TLR4/NF-κB/NLRP3 axis. The results of a current study showed that 4-MU had a potential ability to attenuate the cardiac injury by reducing oxidative stress and inflammation in a TLR4/NF-κB/NLRP3-dependent mechanism.

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

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Acknowledgements

The research and publication of this article were supported by Iran University of Medical Sciences. This article is a part of a PhD’s degree dissertation by Alireza Moradi.

Funding

This work was funded by Iran University of Medical Sciences.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Alireza Moradi, Hamzeh Mirshekari Jahangiri & Nahid Aboutaleb

  2. Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran

    Alireza Moradi, Hamzeh Mirshekari Jahangiri & Nahid Aboutaleb

  3. Lung Diseases Research Center, Ardabil University of Medical Sciences, Ardabil, Iran

    Mohammad Reza Aslani

  4. Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

    Nasim Naderi

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  1. Alireza Moradi
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Contributions

N.A participated in the design and interpretation of the study, data analysis, and the review of the manuscript. A.M, H.M, N.N, and MR.A conducted the experiment and collected the tissue and were responsible for the data analysis. A.M performed histopathological analyses. A.M wrote the manuscript, and all authors reviewed, read, and approved the article. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Nahid Aboutaleb.

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Moradi, A., Aslani, M.R., Mirshekari Jahangiri, H. et al. Protective effects of 4-methylumbelliferone on myocardial ischemia/reperfusion injury in rats through inhibition of oxidative stress and downregulation of TLR4/NF-κB/NLRP3 signaling pathway. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-023-02934-3

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