Sirt1 overexpression improves senescence-associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL-11 transcription

被引：42

作者：

Zhou, Jiawen ^{[1
]}

Chen, Haiyun ^{[2
]}

Wang, Qiuyi ^{[1
]}

Chen, Sihan ^{[1
]}

Wang, Rong ^{[1
]}

Wang, Ziyang ^{[1
]}

Yang, Cuicui ^{[1
]}

Chen, Ao ^{[1
]}

Zhao, Jingyu ^{[1
]}

Zhou, Zihao ^{[1
]}

Mao, Zhiyuan ^{[1
]}

Zuo, Guoping ^{[1
,3
]}

Miao, Dengshun ^{[1
,2
]}

Jin, Jianliang ^{[1
]}

机构：

[1] Nanjing Med Univ, Res Ctr Bone & Stem Cells, Dept Human Anat, Key Lab Aging & Dis,State Key Lab Reprod Med, 101 Longmian Ave, Nanjing 211166, Jiangsu, Peoples R China

[2] Nanjing Med Univ, Friendship Plast Surg Hosp, Antiaging Res Lab, Nanjing, Peoples R China

[3] Nanjing Med Univ, Lab Ctr Basic Med Sci, Nanjing, Peoples R China

来源：

AGING CELL | 2022年 / 21卷 / 08期

基金：

中国国家自然科学基金;

关键词：

cell senescence; IL-11; pulmonary fibroblasts; pulmonary fibrosis; senescence-associated secretory phenotype; Sirt1; Smad2; vitamin D; TO-MESENCHYMAL TRANSITION; LUNG FIBROSIS; BONE LOSS; MICE; ACTIVATION; PROTECTS;

D O I：

10.1111/acel.13680

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-beta 1/IL-11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF-beta 1/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-beta 1/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-beta 1/IL-11/MEK/ERK signaling proteins, and 1,25(OH)(2)D-3 and IL-11 levels were detected in serum. Nine-week-old WT, Sirt1 mesenchymal transgene (Sirt1(Tg)), Cyp27b1(-/-), and Sirt1(Tg)Cyp27b1(-/-) mice were observed the pulmonary function, aging, and senescence-associated secretory phenotype and TGF-beta 1/IL-11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF-beta 1/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-beta 1/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-beta 1/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.

引用

页数：18

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