Journal article
Tumor necrosis factor-alpha promotes and exacerbates calcification in heart valve myofibroblast populations
The FASEB journal, Vol.35(3), pp.e21382-n/a
03/01/2021
DOI: 10.1096/fj.202002013RR
PMCID: PMC7875331
PMID: 33554387
Abstract
Pro-inflammatory cytokines play critical roles in regulating valvular interstitial cell (VIC) phenotypic changes that can cause heart valve fibrosis and calcification. Tumor necrosis factor alpha (TNF-alpha) is a cytokine known to influence VIC behavior and has been reported at high levels in calcified valves ex vivo. We sought to understand the specific effects of TNF-alpha on VIC phenotypes (eg, fibroblast, profibrotic activated myofibroblasts) and its link with heart valve disorders. We characterize human aortic valve tissue from patients with valve disorders and identify a high variability of fibrotic and calcific markers between tissues. These results motivated in vitro studies to explore the effects of TNF-alpha on defined VIC fibroblasts and profibrotic activated myofibroblasts, induced via FGF-2 and TGF-beta 1 treatment. Using 3D hydrogels to culture VICs, we measure the effect of TNF-alpha (0.1-10 ng/mL) on key markers of fibrosis (eg, alpha SMA, COL1A1) and calcification (eg, RUNX2, BMP2, and calcium deposits). We observe calcification in TNF-alpha-treated VIC activated myofibroblasts and identify the MAPK/ERK signaling cascade as a potential pathway for TNF-alpha mediated calcification. Conversely, VIC fibroblasts respond to TNF-alpha with decreased calcification. Treatment of VIC profibrotic activated myofibroblast populations with TNF-alpha leads to increased calcification. Our in vitro findings correlate with findings in diseased human valves and highlight the importance of understanding the effect of cytokines and signaling pathways on specific VIC phenotypes. Finally, we reveal MAPK/ERK as a potential pathway involved in VIC-mediated matrix calcification with TNF-alpha treatment, suggesting this pathway as a potential pharmaceutical target for aortic valve disease.
Details
- Title: Subtitle
- Tumor necrosis factor-alpha promotes and exacerbates calcification in heart valve myofibroblast populations
- Creators
- Andrea Gonzalez Rodriguez - University of Colorado BoulderMegan E. Schroeder - University of Colorado BoulderJoseph C. Grim - University of Colorado BoulderCierra J. Walker - University of Colorado BoulderKelly F. Speckl - University of Colorado BoulderRobert M. Weiss - University of IowaKristi S. Anseth - University of Colorado Boulder
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.35(3), pp.e21382-n/a
- DOI
- 10.1096/fj.202002013RR
- PMID
- 33554387
- PMCID
- PMC7875331
- NLM abbreviation
- FASEB J
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Publisher
- Wiley
- Number of pages
- 17
- Grant note
- RO1HL132353; RO1HL142935; T32 HL007822 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Biological Sciences Initiative Fellowship 18IPA34170040 / American Heart Association
- Language
- English
- Date published
- 03/01/2021
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984359873802771
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