Journal article
Biphasic changes in TGF-beta 1 signaling drive NSAID-induced multi-organ damage
Free radical biology & medicine, Vol.160, pp.125-140
11/20/2020
DOI: 10.1016/j.freeradbiomed.2020.06.026
PMID: 32750407
Abstract
The clinical utility of non-steroidal anti-inflammatory drugs (NSAIDs), used extensively worldwide, is limited by adverse cardiac events resulting from chronic drug exposure. Here, we provide evidence identifying transforming growth factor beta (TGF-beta 1), released from multiple tissues, as a critical driver of NSAID-induced multi organ damage. Biphasic changes in TGF-beta 1 levels in liver and heart were accompanied by ROS generation, cell death, fibrotic remodeling, compromised cardiac contractility and elevated liver enzymes. Pharmacological inhibition of TGF-beta RI signaling markedly improved heart and liver function and increased overall survival of animals exposed to multiple NSAIDs, effects likely mediated by reductions in NOX-dependent ROS generation. Notably, the beneficial impact of TGF-beta RI blockade was confined to a critical window wherein consecutive, but not concurrent, inhibitor administration improved cardiac and hepatic endpoints. Remarkably, in addition to ameliorating indomethacin-mediated myofilament disruptions, cardiac TGF-beta RI knockdown lead to drastic reductions in TGF-beta 1 production accompanied by lessening in intestinal lesioning underscoring the importance of endocrine TGF-beta 1 signaling in NSAID-driven tissue injury. Indeed, gastric ulceration was associated with a higher incidence of cardiac complications in a human cohort underscoring the critical importance of circulation facilitated peripheral organ system interconnectedness in efforts seeking to mitigate the toxic side effects of chronic NSAID use.
Details
- Title: Subtitle
- Biphasic changes in TGF-beta 1 signaling drive NSAID-induced multi-organ damage
- Creators
- Sreemoyee Chakraborti - Sanjay Gandhi Post Graduate Institute of Medical SciencesArnab Pramanick - Sanjay Gandhi Post Graduate Institute of Medical SciencesSudipta Saha - Babasaheb Bhimrao Ambedkar UniversitySubhasish Sarkar - College of Medicine & Sagore Dutta HospitalLaishram Pradeepkumar Singh - University of KalyaniAdele Stewart - Florida Atlantic UniversityBiswanath Maity - Centre of Biomedical Research
- Resource Type
- Journal article
- Publication Details
- Free radical biology & medicine, Vol.160, pp.125-140
- Publisher
- Elsevier
- DOI
- 10.1016/j.freeradbiomed.2020.06.026
- PMID
- 32750407
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Number of pages
- 16
- Grant note
- Centre of Biomedical Research (CBMR) BT/RLF/Re-entry/15/2013 / Ramalingaswami Re-entry Fellowship, Department of Biotechnology, India BT/PR21156/MED/30/1753/2016 / Department of Biotechnology (DBT), India; Department of Biotechnology (DBT) India
- Language
- English
- Date published
- 11/20/2020
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618518602771
Metrics
9 Record Views