TY - JOUR
T1 - The circadian clock regulates rhythmic activation of the NRF2/glutathionemediated antioxidant defense pathway to modulate pulmonary fibrosis
AU - Pekovic-Vaughan, Vanja
AU - Gibbs, Julie
AU - Yoshitane, Hikari
AU - Yang, Nan
AU - Pathiranage, Dharshika
AU - Guo, Baoqiang
AU - Sagami, Aya
AU - Taguchi, Keiko
AU - Bechtold, David
AU - Loudon, Andrew
AU - Yamamoto, Masayuki
AU - Chan, Jefferson
AU - van der Horst, Gijsbertus T.J.
AU - Fukada, Yoshitaka
AU - Meng, Qing Jun
PY - 2014/3/15
Y1 - 2014/3/15
N2 - The disruption of the NRF2 (nuclear factor erythroid-derived 2-like 2)/glutathione-mediated antioxidant defense pathway is a critical step in the pathogenesis of several chronic pulmonary diseases and cancer. While the mechanism of NRF2 activation upon oxidative stress has been widely investigated, little is known about the endogenous signals that regulate the NRF2 pathway in lung physiology and pathology. Here we show that an E-box-mediated circadian rhythm of NRF2 protein is essential in regulating the rhythmic expression of antioxidant genes involved in glutathione redox homeostasis in the mouse lung. Using an in vivo bleomycin-induced lung fibrosis model, we reveal a clock "gated" pulmonary response to oxidative injury, with a more severe fibrotic effect when bleomycin was applied at a circadian nadir in NRF2 levels. Timed administration of sulforaphane, an NRF2 activator, significantly blocked this phenotype. Moreover, in the lungs of the arrhythmic ClockΔ19 mice, the levels of NRF2 and the reduced glutathione are constitutively low, associated with increased protein oxidative damage and a spontaneous fibrotic-like pulmonary phenotype. Our findings reveal a pivotal role for the circadian control of the NRF2/glutathione pathway in combating oxidative/fibrotic lung damage, which might prompt new chronotherapeutic strategies for the treatment of human lung diseases, including idiopathic pulmonary fibrosis.
AB - The disruption of the NRF2 (nuclear factor erythroid-derived 2-like 2)/glutathione-mediated antioxidant defense pathway is a critical step in the pathogenesis of several chronic pulmonary diseases and cancer. While the mechanism of NRF2 activation upon oxidative stress has been widely investigated, little is known about the endogenous signals that regulate the NRF2 pathway in lung physiology and pathology. Here we show that an E-box-mediated circadian rhythm of NRF2 protein is essential in regulating the rhythmic expression of antioxidant genes involved in glutathione redox homeostasis in the mouse lung. Using an in vivo bleomycin-induced lung fibrosis model, we reveal a clock "gated" pulmonary response to oxidative injury, with a more severe fibrotic effect when bleomycin was applied at a circadian nadir in NRF2 levels. Timed administration of sulforaphane, an NRF2 activator, significantly blocked this phenotype. Moreover, in the lungs of the arrhythmic ClockΔ19 mice, the levels of NRF2 and the reduced glutathione are constitutively low, associated with increased protein oxidative damage and a spontaneous fibrotic-like pulmonary phenotype. Our findings reveal a pivotal role for the circadian control of the NRF2/glutathione pathway in combating oxidative/fibrotic lung damage, which might prompt new chronotherapeutic strategies for the treatment of human lung diseases, including idiopathic pulmonary fibrosis.
KW - Bleomycin
KW - Circadian clock
KW - Glutathione
KW - NRF2
KW - Pulmonary fibrosis
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U2 - 10.1101/gad.237081.113
DO - 10.1101/gad.237081.113
M3 - Article
C2 - 24637114
AN - SCOPUS:84896339411
VL - 28
SP - 548
EP - 560
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 6
ER -