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Sirt1 overexpression improves senescence-associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL-11 transcription.
Zhou, Jiawen; Chen, Haiyun; Wang, Qiuyi; Chen, Sihan; Wang, Rong; Wang, Ziyang; Yang, Cuicui; Chen, Ao; Zhao, Jingyu; Zhou, Zihao; Mao, Zhiyuan; Zuo, Guoping; Miao, Dengshun; Jin, Jianliang.
  • Zhou J; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Chen H; Anti-Aging Research Laboratory, Friendship Plastic Surgery Hospital, Nanjing Medical University, Nanjing, China.
  • Wang Q; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Chen S; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Wang R; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Wang Z; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Yang C; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Chen A; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Zhao J; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Zhou Z; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Mao Z; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Zuo G; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • Miao D; The Laboratory Centre for Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • Jin J; Department of Human Anatomy, Research Centre for Bone and Stem Cells, Key Laboratory for Aging & Disease, The State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Aging Cell ; 21(8): e13680, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1992692
ABSTRACT
Determining the mechanism of senescence-associated pulmonary fibrosis is crucial for designing more effective treatments for chronic lung diseases. This study aimed to determine the following whether Sirt1 and serum vitamin D decreased with physiological aging, promoting senescence-associated pulmonary fibrosis by activating TGF-ß1/IL-11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF-ß1/IL-11/MEK/ERK signaling-mediated senescence-associated pulmonary fibrosis in vitamin D-deficient (Cyp27b1-/- ) mice, and whether Sirt1 downregulated IL-11 expression transcribed by TGF-ß1/Smad2 signaling through deacetylating histone at the IL-11 promoter in pulmonary fibroblasts. Bioinformatics analysis with RNA sequencing data from pulmonary fibroblasts of physiologically aged mice was conducted for correlation analysis. Lungs from young and physiologically aged wild-type (WT) mice were examined for cell senescence, fibrosis markers, and TGF-ß1/IL-11/MEK/ERK signaling proteins, and 1,25(OH)2 D3 and IL-11 levels were detected in serum. Nine-week-old WT, Sirt1 mesenchymal transgene (Sirt1Tg ), Cyp27b1-/- , and Sirt1Tg Cyp27b1-/- mice were observed the pulmonary function, aging, and senescence-associated secretory phenotype and TGF-ß1/IL-11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF-ß1/IL-11/MEK/ERK signaling, and promoting senescence-associated pulmonary fibrosis. Sirt1 overexpression improved pulmonary dysfunction, aging, DNA damage, senescence-associated secretory phenotype, and fibrosis through downregulating TGF-ß1/IL-11/MEK/ERK signaling in Cyp27b1-/- mice. Sirt1 negatively regulated IL-11 expression through deacetylating H3K9/14ac mainly at the region from -871 to -724 of IL-11 promoter, also the major binding region of Smad2 which regulated IL-11 expression at the transcriptional level, and subsequently inhibiting TGF-ß1/IL-11/MEK/ERK signaling in pulmonary fibroblasts. This signaling in aging fibroblasts could be a therapeutic target for preventing senescence-associated pulmonary fibrosis induced by vitamin D deficiency.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pulmonary Fibrosis / Vitamin D Deficiency / Interleukin-11 / Sirtuin 1 Topics: Long Covid Limits: Animals Language: English Journal: Aging Cell Year: 2022 Document Type: Article Affiliation country: Acel.13680

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pulmonary Fibrosis / Vitamin D Deficiency / Interleukin-11 / Sirtuin 1 Topics: Long Covid Limits: Animals Language: English Journal: Aging Cell Year: 2022 Document Type: Article Affiliation country: Acel.13680