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

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.

Circadian Rhythms in Cardiovascular Metabolism

“…123 Conversely, REV-ERBα agonists suppress TGF-β1 (transforming growth factor β1)-induced fibroblast-to-myofibroblast transition and profibrotic phenotype. 124,125 Consistent with the knowledge that the CLOCK/BMAL1 heterodimer is immediately upstream of REV-ERBα, mice deficient for BMAL1 in the proximal tubule exhibit increased renal fibrosis in response to stress. 126 Collectively, these observations highlight that critical fibroblast functions are under circadian control.…”

Environmental tobacco smoke exposure exaggerates bleomycin-induced collagen overexpression during pulmonary fibrogenesis

“…Another enzyme tested in this study is lysyl oxidase, a copper-dependent amine oxidase that helps to stabilize the ECM structure via crosslinking collagen and elastin fibers [ 38 ]. Upregulation of lysyl oxidase has been identified from the fibrotic lesion in lung fibrosis patients and in bleomycin-induced lung fibrotic injury [ 39 ]. Upregulated lysyl oxidases during fibrogenesis drive severe crosslinking of collagen and elastin fibers, preventing degradation of fibrous matrix and contributing to irreversible scarring [ 40 ].…”

Rev-erbα agonists suppresses TGFβ1-induced fibroblast-to-myofibroblast transition and pro-fibrotic phenotype in human lung fibroblasts

“…Novel therapies to treat pulmonary fibrosis and other fibrotic diseases are an unmet clinical need that has to be addressed. Emerging studies using preclinical models, in vitro and in vivo, demonstrated the potential of circadian clock-based therapeutics such as Rev-erbα agonists that directly or indirectly target TGFβ signaling to mitigate the progression of PF [ 9 , 10 , 16 ].…”

“…Mounting evidence supports the role circadian clock proteins in the pathobiology of chronic lung diseases including IPF [ 7 – 10 ]. Circadian clocks are endogenous oscillators that control 24-h physiological and behavioral processes in mammals, regulated externally by Zeitgebers (time of feeding, exercise, sleep-wake cycle, etc.)…”

“…Clock mutant ( Clock ∆19 ) and Rev-erbα fibroblast-specific knockout (KO) mice demonstrate worse fibrosis after bleomycin-induced lung injury. Furthermore, treatment with Rev-erbα agonist GSK4112 or SR9009 reduced the fibrotic responses in human lung fibroblasts, ex-vivo lung tissue explant cultures, and prophylactic model of bleomycin-induced lung fibrosis [ 8 – 10 ].…”