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RGS7 balances acetylation/de-acetylation of p65 to control chemotherapy-dependent cardiac inflammation

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Abstract

Cardiotoxicity remains a major limitation in the clinical utility of anthracycline chemotherapeutics. Regulator of G-protein Signaling 7 (RGS7) and inflammatory markers are up-regulated in the hearts of patients with a history of chemotherapy particularly those with reduced left-ventricular function. RGS7 knockdown in either the murine myocardium or isolated murine ventricular cardiac myocytes (VCM) or cultured human VCM provided marked protection against doxorubicin-dependent oxidative stress, NF-κB activation, inflammatory cytokine production, and cell death. In exploring possible mechanisms causally linking RGS7 to pro-inflammatory signaling cascades, we found that RGS7 forms a complex with acetylase Tip60 and deacetylase sirtuin 1 (SIRT1) and controls the acetylation status of the p65 subunit of NF-κB. In VCM, the detrimental impact of RGS7 could be mitigated by inhibiting Tip60 or activating SIRT1, indicating that the ability of RGS7 to modulate cellular acetylation capacity is critical for its pro-inflammatory actions. Further, RGS7-driven, Tip60/SIRT1-dependent cytokines released from ventricular cardiac myocytes and transplanted onto cardiac fibroblasts increased oxidative stress, markers of transdifferentiation, and activity of extracellular matrix remodelers emphasizing the importance of the RGS7–Tip60–SIRT1 complex in paracrine signaling in the myocardium. Importantly, while RGS7 overexpression in heart resulted in sterile inflammation, fibrotic remodeling, and compromised left-ventricular function, activation of SIRT1 counteracted the detrimental impact of RGS7 in heart confirming that RGS7 increases acetylation of SIRT1 substrates and thereby drives cardiac dysfunction. Together, our data identify RGS7 as an amplifier of inflammatory signaling in heart and possible therapeutic target in chemotherapeutic drug-induced cardiotoxicity.

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Acknowledgements

The authors convey our sincere gratitude to DR. Sayan Biswas, MD, Assistant Professor, Department of Forensic Medicine, College of Medicine and Sagore Dutta Hospital, Kolkata, West Bengal for providing the human autopsy samples. The authors are thankful to Aryakul College of Pharmacy & Research, Lucknow for the help in mice experiments. Dr. Pranesh Kumar was appointed as Assistant Professor there before he moved to University of Lucknow.

Funding

We acknowledge funds from Indian Council of Medical Research (ICMR-5/4/1-26/2020-NCD-I and 5/4/1-22/CVD/2022-NCD-I) to BM.

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Authors and Affiliations

  1. Centre of Biomedical Research (CBMR), SGPGI, SGPGI Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India

    Madhuri Basak, Kiran Das, Tarun Mahata, Dinesh Kumar & Biswanath Maity

  2. Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India

    Nupur Nagar & Krishna Mohan Poluri

  3. Institute of Pharmaceutical Sciences, University of Lucknow, Lucknow, Uttar Pradesh, 226025, India

    Pranesh Kumar

  4. Department of Chemistry, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamilnadu, 603203, India

    Priyadip Das

  5. Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, 33458, USA

    Adele Stewart

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  1. Madhuri Basak
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  2. Kiran Das
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Contributions

Conception and design: MB, AS, and BM. Acquisition of data: MB, KD, TM, DK, PK, NN, and KMP. Analysis and interpretation of data: MB, KD, TM, NN, KMP, PK, PD, and AS, BM. Writing or revision of the manuscript: MB, AS, and BM. Study supervision: AS and BM.

Corresponding authors

Correspondence to Adele Stewart or Biswanath Maity.

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Conflict of interest

The authors declare no conflicts of interest.

Ethical approval and consent to participate

Mouse experiments were performed at the Aryakul College of Pharmacy & Research, Lucknow, India under the guidance of Dr. Pranesh Kumar. Animals were procured after obtaining clearance from the college Animal Ethics Committee (1896/PO/Re/S/16/CPCSEA/2021/5). Post-mortem human tissue samples were acquired from the Department of Forensic Medicine, Sagore Dutta Medical College & Hospital, Kolkata, West Bengal after obtaining the ethical clearance from the Centre of Biomedical Research Ethics Committee (Ref: IEC/CBMR/Corr/2020/16/6).

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Madhuri Basak and Kiran Das have equally contributed this work.

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Basak, M., Das, K., Mahata, T. et al. RGS7 balances acetylation/de-acetylation of p65 to control chemotherapy-dependent cardiac inflammation. Cell. Mol. Life Sci. 80, 255 (2023). https://doi.org/10.1007/s00018-023-04895-5

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