Journal article
A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity
Proceedings of the National Academy of Sciences - PNAS, Vol.120(1), pp.e2213537120-e2213537120
01/03/2023
DOI: 10.1073/pnas.2213537120
PMCID: PMC9910480
PMID: 36574707
Abstract
Dose-limiting cardiotoxicity remains a major limitation in the clinical use of cancer chemotherapeutics. Here, we describe a role for Regulator of G protein Signaling 7 (RGS7) in chemotherapy-dependent heart damage, the demonstration for a functional role of RGS7 outside of the nervous system and retina. Though expressed at low levels basally, we observed robust up-regulation of RGS7 in the human and murine myocardium following chemotherapy exposure. In ventricular cardiomyocytes (VCM), RGS7 forms a complex with Ca
/calmodulin-dependent protein kinase (CaMKII) supported by key residues (K412 and P391) in the RGS domain of RGS7. In VCM treated with chemotherapeutic drugs, RGS7 facilitates CaMKII oxidation and phosphorylation and CaMKII-dependent oxidative stress, mitochondrial dysfunction, and apoptosis. Cardiac-specific RGS7 knockdown protected the heart against chemotherapy-dependent oxidative stress, fibrosis, and myocyte loss and improved left ventricular function in mice treated with doxorubicin. Conversely, RGS7 overexpression induced fibrosis, reactive oxygen species generation, and cell death in the murine myocardium that were mitigated following CaMKII inhibition. RGS7 also drives production and release of the cardiokine neuregulin-1, which facilitates paracrine communication between VCM and neighboring vascular endothelial cells (EC), a maladaptive mechanism contributing to VCM dysfunction in the failing heart. Importantly, while RGS7 was both necessary and sufficient to facilitate chemotherapy-dependent cytotoxicity in VCM, RGS7 is dispensable for the cancer-killing actions of these same drugs. These selective myocyte-intrinsic and myocyte-extrinsic actions of RGS7 in heart identify RGS7 as an attractive therapeutic target in the mitigation of chemotherapy-driven cardiotoxicity.
Details
- Title: Subtitle
- A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity
- Creators
- Madhuri Basak - Centre of Biomedical ResearchAbhishek Singh Sengar - Sanjay Gandhi Post Graduate Institute of Medical SciencesKiran Das - Centre of Biomedical ResearchTarun Mahata - Centre of Biomedical ResearchManish Kumar - Centre of Biomedical ResearchDinesh Kumar - Sanjay Gandhi Post Graduate Institute of Medical SciencesSayan Biswas - College of Medicine & Sagore Dutta HospitalSubhasish Sarkar - College of Medicine & Sagore Dutta HospitalPranesh Kumar - Arya Vaidya SalaPriyadip Das - SRM Institute of Science and TechnologyAdele Stewart - Florida Atlantic UniversityBiswanath Maity - Centre of Biomedical Research
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.120(1), pp.e2213537120-e2213537120
- DOI
- 10.1073/pnas.2213537120
- PMID
- 36574707
- PMCID
- PMC9910480
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- DOI: 10.13039/501100001407, name: Department of Biotechnology, Ministry of Science and Technology, India, award: BT/PR28635/MED/30/2145/2019; DOI: 10.13039/501100001411, name: Indian Council of Medical Research, award: 5/4/1-26/2020-NCD-I; DOI: 10.13039/501100001849, name: Defence Research and Development Organisation, award: DG-(TM)/81/48222/LSRB- 307/SH&DD&BD/2017
- Language
- English
- Date published
- 01/03/2023
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618517202771
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