25-Hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway

Ichikawa, Tomohiro; Sugiura, Hiroaki; Koarai, Akira; Kikuchi, Takashi; Hiramatsu, Masataka; Kawabata, Hiroki; Akamatsu, Keiichiro; Hirano, Tsunahiko; Nakanishi, Masayoshi; Matsunaga, Kazuto; Minakata, Yoshiaki; Ichinose, Masakazu

doi:10.1016/j.yexcr.2013.02.014

Cited by 32 publications

(29 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results thus demonstrated that SIRT3 plays a role in regulating the TGF-␤1 signaling. In addition to TGF-␤ signaling, tissue fibrosis can also be promoted by activation of transcription factors like ␤-catenin and NFATc (23)(24)(25)(26). We therefore measured expression of these factors in Sirt3-KO hearts.…”

Section: Resultsmentioning

confidence: 99%

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Sundaresan

Bindu

Pillai

et al. 2016

Molecular and Cellular Biology

166

141

View full text Add to dashboard Cite

Tissue fibrosis is a major cause of organ dysfunction during chronic diseases and aging. A critical step in this process is transforming growth factor ␤1 (TGF-␤1)-mediated transformation of fibroblasts into myofibroblasts, cells capable of synthesizing extracellular matrix. Here, we show that SIRT3 controls transformation of fibroblasts into myofibroblasts via suppressing the profibrotic TGF-␤1 signaling. We found that Sirt3 knockout (KO) mice with age develop tissue fibrosis of multiple organs, including heart, liver, kidney, and lungs but not whole-body SIRT3-overexpressing mice. SIRT3 deficiency caused induction of TGF-␤1 expression and hyperacetylation of glycogen synthase kinase 3␤ (GSK3␤) at residue K15, which negatively regulated GSK3␤ activity to phosphorylate the substrates Smad3 and ␤-catenin. Reduced phosphorylation led to stabilization and activation of these transcription factors regulating expression of the profibrotic genes. SIRT3 deacetylated and activated GSK3␤ and thereby blocked TGF-␤1 signaling and tissue fibrosis. These data reveal a new role of SIRT3 to negatively regulate aging-associated tissue fibrosis and discloses a novel phosphorylation-independent mechanism controlling the catalytic activity of GSK3␤.

show abstract

Section: Resultsmentioning

confidence: 99%

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Sundaresan

Bindu

Pillai

et al. 2016

Molecular and Cellular Biology

166

141

View full text Add to dashboard Cite

show abstract

“…In vitro studies using human fetal lung fibroblasts (HFL-1) suggest that 25-HC also promotes fibroblast mediated tissue remodeling, by increasing α-smooth muscle actin, collagen I, MMP-2, MMP-9, and TGFβ1, via a NF-κB signaling mechanism (Ichikawa, et al, 2013). In primary human airway epithelial cells, 25-HC enhances IL6 and IL8 release after stimulation of TLR3 and may therefore potentiate the innate immune response in chronic airway diseases (Koarai, et al, 2012).…”

Section: Pulmonary Diseasementioning

confidence: 99%

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Yeganeh

Wiechec

Ande

et al. 2014

Pharmacology & Therapeutics

139

129

View full text Add to dashboard Cite

The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer.

show abstract

“…Furthermore, we found that during pneumococcal infection the expression of genes known to regulate transcription of Acta2 differed significantly between resistant and susceptible mice. For example, the candidate gene Ch25h encoded within the QTL on chromosome 19 is known to enhance Acta2 expression and increase TGFβ1 release [47]. We showed that transcription of Ch25h significantly differed between resistant BALB/c and susceptible CBA/Ca during pneumococcal infection and between control animals.…”

Section: Discussionmentioning

confidence: 75%

“…The cellular infiltrates are located predominantly within lung parenchyma of BALB/c mice while in CBA/Ca it accumulates within peribronchial and perivascular areas [3], [9]. Fibroblasts are activated during tissue injury and they can also recognize pathogen-associated molecular patterns (PAMPs) [47]. Rapid activation of TGFβ by parenchymal fibroblasts could explain observed TGFβ-mediated increase in Treg population, a feature of BALB/c infection [21].…”

Section: Discussionmentioning

confidence: 99%

Genetic Factors Regulating Lung Vasculature and Immune Cell Functions Associate with Resistance to Pneumococcal Infection

et al. 2014

View full text Add to dashboard Cite

Streptococcus pneumoniae is an important human pathogen responsible for high mortality and morbidity worldwide. The susceptibility to pneumococcal infections is controlled by as yet unknown genetic factors. To elucidate these factors could help to develop new medical treatments and tools to identify those most at risk. In recent years genome wide association studies (GWAS) in mice and humans have proved successful in identification of causal genes involved in many complex diseases for example diabetes, systemic lupus or cholesterol metabolism. In this study a GWAS approach was used to map genetic loci associated with susceptibility to pneumococcal infection in 26 inbred mouse strains. As a result four candidate QTLs were identified on chromosomes 7, 13, 18 and 19. Interestingly, the QTL on chromosome 7 was located within S. pneumoniae resistance QTL (Spir1) identified previously in a linkage study of BALB/cOlaHsd and CBA/CaOlaHsd F2 intercrosses. We showed that only a limited number of genes encoded within the QTLs carried phenotype-associated polymorphisms (22 genes out of several hundred located within the QTLs). These candidate genes are known to regulate TGFβ signalling, smooth muscle and immune cells functions. Interestingly, our pulmonary histopathology and gene expression data demonstrated, lung vasculature plays an important role in resistance to pneumococcal infection. Therefore we concluded that the cumulative effect of these candidate genes on vasculature and immune cells functions as contributory factors in the observed differences in susceptibility to pneumococcal infection. We also propose that TGFβ-mediated regulation of fibroblast differentiation plays an important role in development of invasive pneumococcal disease. Gene expression data submitted to the NCBI Gene Expression Omnibus Accession No: GSE49533SNP data submitted to NCBI dbSNP Short Genetic Variation http://www.ncbi.nlm.nih.gov/projects/SNP/snp_viewTable.cgi?handle=MUSPNEUMONIA.

show abstract

25-Hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway

Cited by 32 publications

References 50 publications

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Genetic Factors Regulating Lung Vasculature and Immune Cell Functions Associate with Resistance to Pneumococcal Infection

Contact Info

Product

Resources

About