Journal article
RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis
Redox biology, Vol.57, pp.102487-102487
11/01/2022
DOI: 10.1016/j.redox.2022.102487
PMCID: PMC9557029
PMID: 36228439
Abstract
Dose limiting cardiotoxicity remains a major limiting factor in the clinical use of several cancer chemotherapeutics including anthracyclines and the antimetabolite 5-fluorouracil (5-FU). Prior work has demonstrated that chemotherapeutics increase expression of R7 family regulator of G protein signaling (RGS) protein-binding partner Gβ5, which drives myocyte cytotoxicity. However, though several R7 family members are expressed in heart, the exact role of each protein in chemotherapy driven heart damage remains unclear. Here, we demonstrate that RGS11, downregulated in the human heart following chemotherapy exposure, possesses potent anti-apoptotic actions, in direct opposition to the actions of fellow R7 family member RGS6. RGS11 forms a direct complex with the apoptotic kinase CaMKII and stress responsive transcription factor ATF3 and acts to counterbalance the ability of CaMKII and ATF3 to trigger oxidative stress, mitochondrial dysfunction, cell death, and release of the cardiokine neuregulin-1 (NRG1), which mediates pathological intercommunication between myocytes and endothelial cells. Doxorubicin triggers RGS11 depletion in the murine myocardium, and cardiac-specific OE of RGS11 decreases doxorubicin-induced fibrosis, myocyte hypertrophy, apoptosis, oxidative stress, and cell loss and aids in the maintenance of left ventricular function. Conversely, RGS11 knockdown in heart promotes cardiac fibrosis associated with CaMKII activation and ATF3/NRG1 induction. Indeed, inhibition of CaMKII largely prevents the fibrotic remodeling resulting from cardiac RGS11 depletion underscoring the functional importance of the RGS11-CaMKII interaction in the pathogenesis of cardiac fibrosis. These data describe an entirely new role for RGS11 in heart and identify RGS11 as a potential new target for amelioration of chemotherapy-induced cardiotoxicity.
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Details
- Title: Subtitle
- RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis
- Creators
- Kiran Das - Centre of Biomedical ResearchMadhuri Basak - 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 HospitalSuvro Chatterjee - University of BurdwanMahammed Moniruzzaman - University of BurdwanNimai Chandra Saha - University of BurdwanKausik Mondal - University of KalyaniPranesh 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
- Redox biology, Vol.57, pp.102487-102487
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.redox.2022.102487
- PMID
- 36228439
- PMCID
- PMC9557029
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Language
- English
- Date published
- 11/01/2022
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618650902771
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