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Therapeutic efficacies of mitochondria-targeted esculetin and metformin in the improvement of age-associated atherosclerosis via regulating AMPK activation

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A Correction to this article was published on 26 December 2023

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Abstract

Atherosclerosis, in general, is an age-associated cardiovascular disease wherein a progressive decline in mitochondrial function due to aging majorly contributes to the disease development. Mitochondria-derived ROS due to dysregulated endothelial cell function accentuates the progression of atherosclerotic plaque formation. To circumvent this, mitochondrially targeted antioxidants are emerging as potential candidates to combat metabolic abnormalities. Recently, we synthesized an alkyl TPP+ tagged esculetin (Mito-Esc), and in the current study, we investigated the therapeutic efficacies of Mito-Esc and metformin, a well-known anti-diabetic drug, in the amelioration of age-associated plaque formation in the aortas of 12 months aged Apoe−/− and 20 months aged C57BL/6 mice, in comparison to young C57BL/6 control mice. Administration of Mito-Esc or metformin significantly reduced age-induced atherosclerotic lesion area, macrophage polarization, vascular inflammation, and senescence. Further, chronic passaging of human aortic endothelial cells (HAEC) with either Mito-Esc or metformin significantly delayed cellular senescence via the activation of the AMPK-SIRT1/SIRT6 axis. Conversely, depletion of either AMPK/SIRT1/SIRT6 caused premature senescence. Consistent with this, Mito-Esc or metformin treatment attenuated NFkB-mediated inflammatory signaling and enhanced ARE-mediated anti-oxidant responses in comparison to late passage control HAECs. Importantly, culturing of HAECs for several passages with either Mito-Esc or metformin significantly improved mitochondrial function. Overall, Mito-Esc and metformin treatments delay age-associated atherosclerosis by regulating vascular senescence via the activation of AMPK-SIRT1/SIRT6 axis.

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All the data included in the manuscript will be available upon reasonable request.

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Acknowledgements

This work was supported by grant from the Council of Scientific and Industrial Research, India. Pulipaka S, Singuru G, Sahoo S, and Shaikh A acknowledge ICMR and CSIR, New Delhi, India, for the award of research fellowships. Dr. Muralidharan K for providing animals and animal experimentation. The authors sincerely acknowledge 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./2023/153).

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Authors and Affiliations

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

    Sriravali Pulipaka, Gajalakshmi Singuru, Shashikanta Sahoo & Srigiridhar Kotamraju

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

    Sriravali Pulipaka, Gajalakshmi Singuru, Shashikanta Sahoo, Altab Shaikh & 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. Sriravali Pulipaka
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Contributions

PS contributed to the experiments, data analysis, and writing of the manuscript. SG helped in animal experimentation. SS contributed to data analysis and cell culture experiments. AS contributed to the synthesis of Mito-Esc. RT contributed to the technical and purity aspects of Mito-Esc synthesis. SK supervised the whole project, provision of reagents, and other materials required for performing both in vitro and in vivo experiments, data analysis, and the writing of the manuscript.

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Correspondence to Srigiridhar Kotamraju.

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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 PS, SG, AS, RT, and SK) are assigned to CSIR.

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Pulipaka, S., Singuru, G., Sahoo, S. et al. Therapeutic efficacies of mitochondria-targeted esculetin and metformin in the improvement of age-associated atherosclerosis via regulating AMPK activation. GeroScience 46, 2391–2408 (2024). https://doi.org/10.1007/s11357-023-01015-w

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