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

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‐β1/IL‐11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF‐β1/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‐β1/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‐β1/IL‐11/MEK/ERK signaling proteins, and 1,25(OH)2D3 and IL‐11 levels were detected in serum. Nine‐week‐old WT, Sirt1 mesenchymal transgene (Sirt1Tg), Cyp27b1−/−, and Sirt1TgCyp27b1−/− mice were observed the pulmonary function, aging, and senescence‐associated secretory phenotype and TGF‐β1/IL‐11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF‐β1/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‐β1/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‐β1/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.

Bmi‐1 Overexpression Improves Sarcopenia Induced by 1,25(OH)2D3 Deficiency and Downregulates GATA4‐Dependent Rela Transcription

“…(34) Our recent study found that serum 1,25(OH) 2 D 3 levels decreased in physiologically aged mice compared with young mice, and VD deficiency induced senescence-associated pulmonary fibrosis. (33) Several lines of evidence suggest that 1,25(OH) 2 D 3 deficiency results in the development of age-related sarcopenia by inducing oxidative stress, muscle cell senescence, and SASP and by inhibiting skeletal muscle regeneration. (32,(35)(36)(37) Low 1,25(OH) 2 D 3 status is associated with decreased muscle strength and mass, which is improved by 1,25(OH) 2 D 3 supplementation, especially for an older population at high risk of sarcopenia.…”

“…Staining was performed as previously described. ( 4,33 ) Primary antibodies against NF‐κB‐p65 (No. 8242; Cell Signaling Technology, Beverly, MA, USA), IL‐1β (sc‐52012; Santa Cruz Biotechnology, Dallas, TX, USA), IL‐6 (sc‐1265; Santa Cruz Biotechnology Inc.), TNF‐α (sc‐52746; Santa Cruz Biotechnology), ATM (No.…”

“…Western blots were generated as previously described. ( 33 ) Primary antibodies against Bmi‐1 (No. 66161–1; Proteintech), RING1B (No.…”

“…ChIP was performed using a Magna ChIP™ Chromatin Immunoprecipitation A kit (2931149; Millipore, Billerica, MA, USA) using C2C12 cells following the manufacturer's instructions as previously described. ( 33 ) Antibodies against GATA4 (No. 19530; Proteintech) and rabbit IgG (No.…”

Role of Vitamin D Deficiency in the Pathogenesis of Cardiovascular and Cerebrovascular Diseases

“…Importantly, there is initial evidence that VitD contributes to the regulation of epigenetic mechanisms of aging and that VitD supplementation decelerates epigenetic aging in subjects with VDD [ 189 , 190 ]. Other mechanisms of aging that may be affected by VDD include sirtuin pathways [ 191 ] and cellular senescence [ 192 ]. There is also evidence supporting an association between VDD and frailty in aging [ 193 ].…”