Journal article
Cardiac RGS7 and RGS11 drive TGFβ1-dependent liver damage following chemotherapy exposure
The FASEB journal, Vol.37(8), pp.e23064-n/a
08/2023
DOI: 10.1096/fj.202300094R
PMID: 37440271
Abstract
Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin-induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin-treated cardiomyocytes secrete the endocrine factors transforming growth factor β1 (TGFβ1) and TGFβ superfamily binding protein follistatin-related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFβ1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFβ1 from the heart and the profibrotic and pro-oxidant actions of TGFβ1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.
Details
- Title: Subtitle
- Cardiac RGS7 and RGS11 drive TGFβ1-dependent liver damage following chemotherapy exposure
- Creators
- Kiran Das - Centre of Biomedical ResearchMadhuri Basak - Centre of Biomedical ResearchTarun Mahata - Centre of Biomedical ResearchSayan Biswas - College of Medicine & Sagore Dutta HospitalSukhes Mukherjee - All India Institute of Medical Sciences BhopalPranesh Kumar - University of LucknowMahammed Moniruzzaman - University of BurdwanAdele Stewart - Florida Atlantic UniversityBiswanath Maity - Centre of Biomedical Research
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.37(8), pp.e23064-n/a
- DOI
- 10.1096/fj.202300094R
- PMID
- 37440271
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Grant note
- 5/4/1-26/2020-NCD-I / Indian Council of Medical Research (ICMR) 5/4/1-22/CVD/2022 NCD-I / Indian Council of Medical Research (ICMR) CBMR/IMR/0012/2021 / Centre of Biomedical Research Department of Medical Education, Uttar Pradesh Government
- Language
- English
- Date published
- 08/2023
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618649902771
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