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Mitochondria targeted esculetin administration improves insulin resistance and hyperglycemia-induced atherosclerosis in db/db mice

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Abstract

The development and progression of hyperglycemia (HG) and HG-associated atherosclerosis are exacerbated by mitochondrial dysfunction due to dysregulated mitochondria-derived ROS generation. We recently synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and tested its dose–response therapeutic efficacy in mitigating HG-induced atherosclerosis in db/db mice. In comparison to simvastatin and pioglitazone, Mito-Esc administration resulted in a considerable reduction in body weights and improved glucose homeostasis, possibly by reducing hepatic gluconeogenesis, as indicated by a reduction in glycogen content, non-esterified free fatty acids (NEFA) levels, and fructose 1,6-bisphosphatase (FBPase) activity. Interestingly, Mito-Esc treatment, by regulating phospho-IRS and phospho-AKT levels, greatly improved palmitate-induced insulin resistance, resulting in enhanced glucose uptake in adipocytes and HepG2 cells. Also, and importantly, Mito-Esc administration prevented HG-induced atheromatous plaque formation and lipid accumulation in the descending aorta. In addition, Mito-Esc administration inhibited the HG-mediated increase in VACM, ICAM, and MAC3 levels in the aortic tissue, as well as reduced the serum pro-inflammatory cytokines and markers of senescence. In line with this, Mito-Esc significantly inhibited monocyte adherence to human aortic endothelial cells (HAECs) treated with high glucose and reduced high glucose-induced premature senescence in HAECs by activating the AMPK-SIRT1 pathway. In contrast, Mito-Esc failed to regulate high glucose-induced endothelial cell senescence under AMPK/SIRT1-depleted conditions. Together, the therapeutic efficacy of Mito-Esc in the mitigation of hyperglycemia-induced insulin resistance and the associated atherosclerosis is in part mediated by potentiating the AMPK-SIRT1 axis.

Key messages

  • Mito-Esc administration significantly mitigates diabetes-induced atherosclerosis.

  • Mito-Esc improves hyperglycemia (HG)-associated insulin resistance.

  • Mito-Esc inhibits HG-induced vascular senescence and inflammation in the aorta.

  • Mito-Esc-mediated activation of the AMPK-SIRT1 axis regulates HG-induced endothelial cell senescence.

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Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors acknowledge Dr. Lakshma Nayak for FACS analysis, Dr. Madhusudana Kuncha for HbA1c levels, and Dr. Muralidharan K for providing animals and animal experimentation. Also, the authors sincerely acknowledge the late Dr. Surendar Reddy Bathula, who was instrumental in designing the process for the synthesis of Mito-Esc. He lost his battle for life due to COVID-19-related complications. We thank the Department of Knowledge and Information Management, CSIR-IICT, Hyderabad, India, for performing the plagiarism check of this manuscript (IICT/Pubs./2023/394).

Funding

This work was supported by internal funding to SK from the Council of Scientific and Industrial Research, India. Singuru G, Pulipaka S, Shaikh A, Sahoo S, and Jangam A acknowledge ICMR and CSIR, New Delhi, India, for the award of research fellowships.

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Authors and Affiliations

  1. Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India

    Gajalakshmi Singuru, Sriravali Pulipaka, Shashikanta Sahoo, Aruna Jangam & Srigiridhar Kotamraju

  2. Academy of Scientific and Innovative Research, Ghaziabad, 201002, India

    Gajalakshmi Singuru, Sriravali Pulipaka, Altab Shaikh, Shashikanta Sahoo, Aruna Jangam & Srigiridhar Kotamraju

  3. Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India

    Altab Shaikh

  4. High Impact Innovations-Sustainable Health Solutions (HISHS), Sun Pharmaceutical Industries Ltd., Vadodara, 390012, India

    Rajamannar Thennati

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  1. Gajalakshmi Singuru
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Contributions

G.S. contributed to the experimental design, data analysis, and writing of the manuscript. S.P. contributed to the SA β-gal assay. A.S. contributed to the synthesis of Mito-Esc. S.S. contributed to the HAEC-monocyte adhesion assay. A.J. contributed to breeding animals. R.T. contributed to the technical and purity aspects of Mito-Esc synthesis. S.K. supervised the whole project, the provision of reagents, and other materials required for performing both in vitro and in vivo experiments, data analysis, and the writing of the manuscript.

Corresponding author

Correspondence to Srigiridhar Kotamraju.

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Ethics approval and consent to participate

The mice study performed in this work was reviewed and approved by the Institutional Animal Ethical Committee (IICT/IAEC/52/2018) according to the guidelines formulated for the care and use of animals in scientific research (ICMR, India) at a Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA)-registered animal facility.

Conflict of interest

The authors declare the following competing financial interest(s): patents and patent applications describing Mito-Esc for its biological properties (with inventors S.G, P.S, A.S, R.T, and S.K) are assigned to CSIR.

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Singuru, G., Pulipaka, S., Shaikh, A. et al. Mitochondria targeted esculetin administration improves insulin resistance and hyperglycemia-induced atherosclerosis in db/db mice. J Mol Med (2024). https://doi.org/10.1007/s00109-024-02449-1

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