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13. The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis

Author

Pekovic-Vaughan, Vanja, Gibbs, Julie, Yoshitane, Hikari, Yang, Nan, Pathiranage, Dharshika, Guo, Baoqiang, Sagami, Aya, Taguchi, Keiko, Bechtold, David, Loudon, Andrew, Yamamoto, Masayuki, Chan, Jefferson, van der Horst, Gijsbertus TJ, Fukada, Yoshitaka, and Meng, Qing-Jun

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Sleep Research, Lung, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, 1.1 Normal biological development and functioning, Respiratory, Animals, Anticarcinogenic Agents, Bleomycin, Circadian Clocks, E-Box Elements, Female, Gene Expression Regulation, Glutathione, Homeostasis, Isothiocyanates, Mice, Mice, Inbred C57BL, NF-E2-Related Factor 2, Oxidative Stress, Promoter Regions, Genetic, Protein Binding, Pulmonary Fibrosis, Sulfoxides, circadian clock, glutathione, NRF2, bleomycin, pulmonary fibrosis, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

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 Clock(Δ19) 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.

Published
2014

15. Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus

Author

Saito, Ryo, Koebis, Michinori, Nagai, Taku, Shimizu, Kimiko, Liao, Jingzhu, Wulaer, Bolati, Sugaya, Yuki, Nagahama, Kenichiro, Uesaka, Naofumi, Kushima, Itaru, Mori, Daisuke, Maruyama, Kazuaki, Nakao, Kazuki, Kurihara, Hiroki, Yamada, Kiyofumi, Kano, Masanobu, Fukada, Yoshitaka, Ozaki, Norio, and Aiba, Atsu

Published
2020
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21. Na+/Ca2+ exchanger mediates cold Ca2+ signaling conserved for temperature-compensated circadian rhythms

Author

KON, NAOHIRO, WANG, HSIN-TZU, S., KATO YOSHIAKI, UEMOTO, KYOUHEI, KAWAMOTO, NAOHIRO, KAWASAKI, KOJI, ENOKI, RYOSUKE, KUROSAWA, GEN, NAKANE, TATSUTO, SUGIYAMA, YASUNORI, TAGASHIRA, HIDEAKI, ENDO, MOTOMU, IWASAKI, HIDEO, IWAMOTO, TAKAHIRO, KUME, KAZUHIKO, FUKADA, YOSHITAKA, KON, NAOHIRO, WANG, HSIN-TZU, S., KATO YOSHIAKI, UEMOTO, KYOUHEI, KAWAMOTO, NAOHIRO, KAWASAKI, KOJI, ENOKI, RYOSUKE, KUROSAWA, GEN, NAKANE, TATSUTO, SUGIYAMA, YASUNORI, TAGASHIRA, HIDEAKI, ENDO, MOTOMU, IWASAKI, HIDEO, IWAMOTO, TAKAHIRO, KUME, KAZUHIKO, and FUKADA, YOSHITAKA

Abstract

Circadian rhythms are based on biochemical oscillations generated by clock genes/proteins, which independently evolved in animals, fungi, plants, and cyanobacteria. Temperature compensation of the oscillation speed is a common feature of the circadian clocks, but the evolutionary-conserved mechanism has been unclear. Here, we show that Na+/Ca2+ exchanger (NCX) mediates cold-responsive Ca2+ signaling important for the temperature-compensated oscillation in mammalian cells. In response to temperature decrease, NCX elevates intracellular Ca2+, which activates Ca2+/calmodulin-dependent protein kinase II and accelerates transcriptional oscillations of clock genes. The cold-responsive Ca2+ signaling is conserved among mice, Drosophila, and Arabidopsis. The mammalian cellular rhythms and Drosophila behavioral rhythms were severely attenuated by NCX inhibition, indicating essential roles of NCX in both temperature compensation and autonomous oscillation. NCX also contributes to the temperature-compensated transcriptional rhythms in cyanobacterial clock. Our results suggest that NCX-mediated Ca2+ signaling is a common mechanism underlying temperature-compensated circadian rhythms both in eukaryotes and prokaryotes.

Published
2023

30. The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Author

Dudek, Michal, Gossan, Nicole, Yang, Nan, Im, Hee-Jeong, Ruckshanthi, Jayalath P.D., Yoshitane, Hikari, Li, Xin, Jin, Ding, Wang, Ping, Boudiffa, Maya, Bellantuono, Ilaria, Fukada, Yoshitaka, Boot- Handford, Ray P., and Meng, Qing-Jun

Subjects
Homeostasis -- Research -- Genetic aspects, Osteoarthritis -- Research -- Genetic aspects -- Development and progression -- Care and treatment -- Patient outcomes, Health care industry
Abstract

Osteoarthritis (OA) is the most prevalent and debilitating joint disease, and there are currently no effective disease- modifying treatments available. Multiple risk factors for OA, such as aging, result in progressive damage and loss of articular cartilage. Autonomous circadian clocks have been identified in mouse cartilage, and environmental disruption of circadian rhythms in mice predisposes animals to OA-like damage. However, the contribution of the cartilage clock mechanisms to the maintenance of tissue homeostasis is still unclear. Here, we have shown that expression of the core clock transcription factor BMAL1 is disrupted in human OA cartilage and in aged mouse cartilage. Furthermore, targeted Bmall ablation in mouse chondrocytes abolished their circadian rhythm and caused progressive degeneration of articular cartilage. We determined that BMAL1 directs the circadian expression of many genes implicated in cartilage homeostasis, including those involved in catabolic, anabolic, and apoptotic pathways. Loss of BMAL1 reduced the levels of phosphorylated SMAD2/3 (p-SMAD2/3) and NFATC2 and decreased expression of the major matrix-related genes Sox9, Acan, and Col2a1, but increased p-SMAD1/5 levels. Together, these results define a regulatory mechanism that links chondrocyte BMAL1 to the maintenance and repair of cartilage and suggest that circadian rhythm disruption is a risk factor for joint diseases such as OA., Introduction Osteoarthritis (OA) is one of the most common joint diseases, causing severe pain and disability, with no effective disease-modifying drugs currently available. One key feature of OA is the [...]

Published
2016
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45. Na+/Ca2+ exchanger mediates cold Ca2+ signaling conserved for temperature-compensated circadian rhythms

Author

KON, NAOHIRO, WANG, HSIN-TZU, S. KATO, YOSHIAKI, UEMOTO, KYOUHEI, KAWAMOTO, NAOHIRO, KAWASAKI, KOJI, ENOKI, RYOSUKE, KUROSAWA, GEN, NAKANE, TATSUTO, SUGIYAMA, YASUNORI, TAGASHIRA, HIDEAKI, ENDO, MOTOMU, IWASAKI, HIDEO, IWAMOTO, TAKAHIRO, KUME, KAZUHIKO, FUKADA, YOSHITAKA, KON, NAOHIRO, WANG, HSIN-TZU, S. KATO, YOSHIAKI, UEMOTO, KYOUHEI, KAWAMOTO, NAOHIRO, KAWASAKI, KOJI, ENOKI, RYOSUKE, KUROSAWA, GEN, NAKANE, TATSUTO, SUGIYAMA, YASUNORI, TAGASHIRA, HIDEAKI, ENDO, MOTOMU, IWASAKI, HIDEO, IWAMOTO, TAKAHIRO, KUME, KAZUHIKO, and FUKADA, YOSHITAKA

Abstract

Circadian rhythms are based on biochemical oscillations generated by clock genes/proteins, which independently evolved in animals, fungi, plants, and cyanobacteria. Temperature compensation of the oscillation speed is a common feature of the circadian clocks, but the evolutionary-conserved mechanism has been unclear. Here, we show that Na+/Ca2+ exchanger (NCX) mediates cold-responsive Ca2+ signaling important for the temperature-compensated oscillation in mammalian cells. In response to temperature decrease, NCX elevates intracellular Ca2+, which activates Ca2+/calmodulin-dependent protein kinase II and accelerates transcriptional oscillations of clock genes. The cold-responsive Ca2+ signaling is conserved among mice, Drosophila, and Arabidopsis. The mammalian cellular rhythms and Drosophila behavioral rhythms were severely attenuated by NCX inhibition, indicating essential roles of NCX in both temperature compensation and autonomous oscillation. NCX also contributes to the temperature-compensated transcriptional rhythms in cyanobacterial clock. Our results suggest that NCX-mediated Ca2+ signaling is a common mechanism underlying temperature-compensated circadian rhythms both in eukaryotes and prokaryotes., identifier:2375-2548

Published
2021

46. Attenuated SIRT1 Activity Leads to PER2 Cytoplasmic Localization and Dampens the Amplitude of Bmal1 Promoter-Driven Circadian Oscillation

Author

Ashimori, Atsushige, Nakahata, Yasukazu, Sato, Toshiya, Fukamizu, Yuichiro, Matsui, Takaaki, Yoshitane, Hikari, Fukada, Yoshitaka, Shinohara, Kazuyuki, Bessho, Yasumasa, Ashimori, Atsushige, Nakahata, Yasukazu, Sato, Toshiya, Fukamizu, Yuichiro, Matsui, Takaaki, Yoshitane, Hikari, Fukada, Yoshitaka, Shinohara, Kazuyuki, and Bessho, Yasumasa

Abstract

The circadian clock possesses robust systems to maintain the rhythm approximately 24 h, from cellular to organismal levels, whereas aging is known to be one of the risk factors linked to the alternation of circadian physiology and behavior. The amount of many metabolites in the cells/body is altered with the aging process, and the most prominent metabolite among them is the oxidized form of nicotinamide adenine dinucleotide (NAD+), which is associated with posttranslational modifications of acetylation and poly-ADP-ribosylation status of circadian clock proteins and decreases with aging. However, how low NAD+ condition in cells, which mimics aged or pathophysiological conditions, affects the circadian clock is largely unknown. Here, we show that low NAD+ in cultured cells promotes PER2 to be retained in the cytoplasm through the NAD+/SIRT1 axis, which leads to the attenuated amplitude of Bmal1 promoter-driven luciferase oscillation. We found that, among the core clock proteins, PER2 is mainly affected in its subcellular localization by NAD+ amount, and a higher cytoplasmic PER2 localization was observed under low NAD+ condition. We further found that NAD+-dependent deacetylase SIRT1 is the regulator of PER2 subcellular localization. Thus, we anticipate that the altered PER2 subcellular localization by low NAD+ is one of the complex changes that occurs in the aged circadian clock., Frontiers in Neuroscience, 15, art. no. 647589; 2021

Published
2021

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