Circadian clock molecule REV-ERBα regulates lung fibrotic progression through collagen stabilization

Qixin Wang, Isaac Kirubakaran Sundar, Joseph H. Lucas, Jun-Gyu Park, Aitor Nogales, Luis Martinez-Sobrido and Irfan Rahman ()
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Qixin Wang: University of Rochester Medical Center
Isaac Kirubakaran Sundar: University of Kansas Medical Center
Joseph H. Lucas: University of Rochester Medical Center
Jun-Gyu Park: Texas Biomedical Research Institute, Disease Intervention and Prevention Program
Aitor Nogales: Texas Biomedical Research Institute, Disease Intervention and Prevention Program
Luis Martinez-Sobrido: Texas Biomedical Research Institute, Disease Intervention and Prevention Program
Irfan Rahman: University of Rochester Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Molecular clock REV-ERBα is central to regulating lung injuries, and decreased REV-ERBα abundance mediates sensitivity to pro-fibrotic insults and exacerbates fibrotic progression. In this study, we determine the role of REV-ERBα in fibrogenesis induced by bleomycin and Influenza A virus (IAV). Bleomycin exposure decreases the abundance of REV-ERBα, and mice dosed with bleomycin at night display exacerbated lung fibrogenesis. Rev-erbα agonist (SR9009) treatment prevents bleomycin induced collagen overexpression in mice. Rev-erbα global heterozygous (Rev-erbα Het) mice infected with IAV showed augmented levels of collagens and lysyl oxidases compared with WT-infected mice. Furthermore, Rev-erbα agonist (GSK4112) prevents collagen and lysyl oxidase overexpression induced by TGFβ in human lung fibroblasts, whereas the Rev-erbα antagonist exacerbates it. Overall, these results indicate that loss of REV-ERBα exacerbates the fibrotic responses by promoting collagen and lysyl oxidase expression, whereas Rev-erbα agonist prevents it. This study provides the potential of Rev-erbα agonists in the treatment of pulmonary fibrosis.

Date: 2023
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DOI: 10.1038/s41467-023-36896-0

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