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GSK-3α aggravates inflammation, metabolic derangement, and cardiac injury post-ischemia/reperfusion

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Abstract

Reperfusion after acute myocardial infarction further exaggerates cardiac injury and adverse remodeling. Irrespective of cardiac cell types, loss of specifically the α isoform of the protein kinase GSK-3 is protective in chronic cardiac diseases. However, the role of GSK-3α in clinically relevant ischemia/reperfusion (I/R)-induced cardiac injury is unknown. Here, we challenged cardiomyocyte-specific conditional GSK-3α knockout (cKO) and littermate control mice with I/R injury and investigated the underlying molecular mechanism using an in vitro GSK-3α gain-of-function model in AC16 cardiomyocytes post-hypoxia/reoxygenation (H/R). Analysis revealed a significantly lower percentage of infarct area in the cKO vs. control hearts post-I/R. Consistent with in vivo findings, GSK-3α overexpression promoted AC16 cardiomyocyte death post-H/R which was accompanied by an induction of reactive oxygen species (ROS) generation. Consistently, GSK-3α gain-of-function caused mitochondrial dysfunction by significantly suppressing mitochondrial membrane potential. Transcriptomic analysis of GSK-3α overexpressing cardiomyocytes challenged with hypoxia or H/R revealed that NOD-like receptor (NLR), TNF, NF-κB, IL-17, and mitogen-activated protein kinase (MAPK) signaling pathways were among the most upregulated pathways. Glutathione and fatty acid metabolism were among the top downregulated pathways post-H/R. Together, these observations suggest that loss of cardiomyocyte-GSK-3α attenuates cardiac injury post-I/R potentially through limiting the myocardial inflammation, mitochondrial dysfunction, and metabolic derangement. Therefore, selective inhibition of GSK-3α may provide beneficial effects in I/R-induced cardiac injury and remodeling.

Key messages

  • GSK-3α promotes cardiac injury post-ischemia/reperfusion (I/R).

  • GSK-3α regulates inflammatory and metabolic pathways post-hypoxia/reoxygenation (H/R).

  • GSK-3α overexpression upregulates NOD-like receptor (NLR), TNF, NF-kB, IL-17, and MAPK signaling pathways in cardiomyocytes post-H/R.

  • GSK-3α downregulates glutathione and fatty acid metabolic pathways in cardiomyocytes post-H/R.

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Data availability

Data is included in the manuscript and supplementary files. All the raw data is deposited in the NCBI database with the accession number PRJNA984601.

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Funding

The work was supported by collaborative (22010901112) research grants from the University of Sharjah to Firdos Ahmad.

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Authors and Affiliations

  1. Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, UAE

    Firdos Ahmad & Rizwan Qaisar

  2. Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, UAE

    Firdos Ahmad, Hezlin Marzook, Anamika Gupta, Aseel Aref, Mohamed A. Saleh & Rizwan Qaisar

  3. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, 37240, USA

    Firdos Ahmad

  4. LifeBytes India Pvt Ltd., Brigade Triumph, Hebbal Kempapura, Bengaluru, Karnataka, 560092, India

    Kiran Patil

  5. Department of Applied Biology, College of Science, University of Sharjah, Sharjah, 27272, UAE

    Amir Ali Khan

  6. BioGrad Biobank, 61 Stephenson Way, Liverpool, L13 1HN, UK

    Amir Ali Khan

  7. Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, UAE

    Mohamed A. Saleh

  8. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Mohamed A. Saleh

  9. Department of Surgery, Duke University School of Medicine, Durham, NC, 27710, USA

    Walter J. Koch

  10. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada

    James R. Woodgett

  11. Department of Medical Biophysics, University of Toronto, Toronto, Canada

    James R. Woodgett

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  1. Firdos Ahmad
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Contributions

FA designed the study, performed experiments, acquired funding, supervised the project, performed data analysis and interpretation, and wrote the manuscript. HM performed experiments, collected data, and helped with manuscript writing. AA and AG performed experiments and collected data. AAK and MAS helped with data analysis, interpretation, and manuscript writing. WJK and JRW helped with reagents, data analysis, and manuscript editing. RQ helped with data analysis, interpretation, and supervision.

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Correspondence to Firdos Ahmad.

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The Institutional Animal Care and Use Committee (IACUC) of Vanderbilt University Medical Center approved all animal procedures and treatments.

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Ahmad, F., Marzook, H., Gupta, A. et al. GSK-3α aggravates inflammation, metabolic derangement, and cardiac injury post-ischemia/reperfusion. J Mol Med 101, 1379–1396 (2023). https://doi.org/10.1007/s00109-023-02373-w

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