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Cited by 38Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisCaveolin-1 and cellular processesEpigenetics and DNA Methylation

Epigenetic Regulation of Caveolin-1 Gene Expression in Lung Fibroblasts

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Sanders, Yan Y., Liu, Hui, Scruggs, Anne M., Duncan, Steven R., Huang, Steven K., Thannickal, Victor J.·2017·American Journal of Respiratory Cell and Molecular Biology
DOI 10.1165/rcmb.2016-0034ocPMC PMC5248956
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Abstract

Fibrotic disorders are associated with tissue accumulation of fibroblasts. We recently showed that caveolin (Cav)-1 gene suppression by a profibrotic cytokine, transforming growth factor (TGF)-β1, contributes to fibroblast proliferation and apoptosis resistance. Cav-1 has been shown to be constitutively suppressed in idiopathic pulmonary fibrosis (IPF), but mechanisms for this suppression are incompletely understood. We hypothesized that epigenetic processes contribute to Cav-1 down-regulation in IPF lung fibroblasts, and after fibrogenic stimuli. Cav-1 expression levels, DNA methylation status, and histone modifications associated with the Cav-1 promoter were examined by PCR, Western blots, pyrosequencing, or chromatin immunoprecipitation assays in IPF lung fibroblasts, normal fibroblasts after TGF-β1 stimulation, or in murine lung fibroblasts after bleomycin injury. Methylation-specific PCR demonstrated methylated and unmethylated Cav-1 DNA copies in all groups. Despite significant changes in Cav-1 expression, no changes in DNA methylation were observed in CpG islands or CpG island shores of the Cav-1 promoter by pyrosequencing of lung fibroblasts from IPF lungs, in response to TGF-β1, or after bleomycin-induced murine lung injury, when compared with respective controls. In contrast, the association of Cav-1 promoter with the active histone modification mark, H3 lysine 4 trimethylation, correlated with Cav-1 down-regulation in activated/fibrotic lung fibroblasts. Our data indicate that Cav-1 gene silencing in lung fibroblasts is actively regulated by epigenetic mechanisms that involve histone modifications, in particular H3 lysine 4 trimethylation, whereas DNA methylation does not appear to be a primary mechanism. These findings support therapeutic strategies that target histone modifications to restore Cav-1 expression in fibroblasts participating in pathogenic tissue remodeling.

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  • Augmentation of endogenous Cav-1 levels and supplementation of exogenous caveolin scaffolding domain peptide have been shown to suppress lung fibrosis.

    “Augmentation of endogenous Cav-1 levels and supplementation of exogenous caveolin scaffolding domain (CSD) peptide have been shown to suppress lung fibrosis7,10,11,13,14.”

    From Inhaled LTI-03 for idiopathic pulmonary fibrosis: a randomized dose escalation study (2026) · cites this paper as [10]

    The Abstract reports that restoring Cav-1 with a peptide or adenoviral gene transfer decreased fibrotic changes in cells or tissues. Its Clinical Relevance passage proposes augmenting Cav-1 expression in idiopathic pulmonary fibrosis, but the paper does not show that augmenting endogenous Cav-1 suppresses lung fibrosis; the restoration evidence is not stated as specific to lung fibrosis. (LLM, conf=0.84)

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  • Cav-1 expression in pulmonary fibroblasts and alveolar epithelial cells is decreased in transgenic and rodent bleomycin models of lung injury and in the lungs of patients with IPF.

    “Cav-1 expression in pulmonary fibroblasts and alveolar epithelial cells is decreased in transgenic and rodent bleomycin models of lung injury and in the lungs of patients with IPF10–12.”

    From Inhaled LTI-03 for idiopathic pulmonary fibrosis: a randomized dose escalation study (2026) · cites this paper as [10]

    The Results report decreased Cav-1 in isolated lung fibroblasts and whole-lung samples after bleomycin injury in mice; the Discussion reports decreased expression in most fibroblasts from patients with IPF. Our copy does not establish the decrease in alveolar epithelial cells or in a transgenic lung-injury model. It also reports IPF fibroblast findings rather than a measurement across patients’ whole lungs. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Sanders, Y. Y., Liu, H., Scruggs, A. M., Duncan, S. R., Huang, S. K., & Thannickal, V. J.
Affiliations
  • University of Alabama at Birmingham (US)
  • University of Michigan (US)
Corresponding author
Sanders, Yan Y.
ORCID
Venue
American Journal of Respiratory Cell and Molecular Biology
Publisher
Oxford University Press (OUP)
Published
2017-01-01
Volume
56
Issue
1
Pages
50-61
ISSN
  • 1044-1549 (ISSN-L)
  • 1535-4989
DOI
10.1165/rcmb.2016-0034oc
PMC
PMC5248956
OpenAlex
W2514831580
Cited by
38
References
2
Citations by year
2026: 3 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 6
FWCI
4.47
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX003056)
  • American Thoracic Society
  • Coalition for Pulmonary Fibrosis
  • Pulmonary Fibrosis Foundation
  • National Institutes of Health (HL114470)
  • National Heart, Lung, and Blood Institute (R01HL127203, P01HL114470)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
caveolin-1, idiopathic pulmonary fibrosis, lung fibroblasts, epigenetic regulation, histone modifications, DNA methylation, TGF-β1, bleomycin-induced lung injury, gene silencing, fibroblast activation
MeSH terms
Animals, Base Sequence, Cell Separation, Cells, Cultured, Fibroblasts, Histones, Humans, Lung, Lysine, Mice, Inbred C57BL, Promoter Regions, Genetic, Protein Processing, Post-Translational, Down-Regulation, CpG Islands, DNA Methylation, Histone Code, Epigenesis, Genetic, Caveolin 1, Transforming Growth Factor beta1

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