Sirtuin 4 accelerates heart failure development by enhancing reactive oxygen species-mediated profibrotic transcriptional signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA980290 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24832746_1.fastq.gz | Fastqsanger.gz | |||
| SRR24832746_2.fastq.gz | Fastqsanger.gz | |||
| SRR24832747_1.fastq.gz | Fastqsanger.gz | |||
| SRR24832747_2.fastq.gz | Fastqsanger.gz | |||
| SRR24832748_1.fastq.gz | Fastqsanger.gz |
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Project description:Sirtuin 4 (SIRT4) is a mitochondrially-localized stress-responsive NAD+-dependent deacylase predominantly regulating energy metabolism and ROS homeostasis. While SIRT4 has been implicated in pathological cardiac hypertrophy, underlying mechanisms remain incompletely understood. Here, we show that myocardial expression of SIRT4 was decreased in individuals with severe dilated cardiomyopathy (-73%) but was relatively higher in subjects with concomitant type 2 diabetes (T2D; +56%). To evaluate consequences and mechanisms of altered myocardial SIRT4 expression, mice with global Sirt4 deletion (Sirt4-/-) or cardiomyocyte-specific Sirt4 overexpression (cSirt4-Tg) underwent transverse aortic constriction (TAC) or sham procedures. Cardiac structure and function were similar in Sirt4-/- and WT mice 12 weeks following TAC, whereas cSirt4-Tg mice displayed aggravated cardiac dilation, dysfunction, and fibrosis following TAC. Transcriptional analysis using RNA sequencing revealed synergistic upregulation of collagens and profibrotic regulators in TAC-treated cSirt4-Tg mice, including transforming growth factor beta (TGF), connective tissue growth factor (CTGF), or follistatin-like 1 (Fstl1). These alterations were reversed by mitochondria-targeted antioxidant treatment using MitoQ, along with attenuation of cardiac dysfunction and remodeling, and reversal of tissue fibrosis. SIRT4 overexpression may drive oxidative stress and fibrotic signaling via synergistically increased NOX4 expression (> 7-fold), and/or direct modulation of SIRT4 targets newly identified by protoarray experiments, including calcitonin gene-related peptide (CGRP) receptor component protein (RCP), cyclophilin A, and interleukin-2 receptor β. Thus, SIRT4 overexpression aggravates cardiac remodeling and dysfunction in response to chronic pressure overload by ROS-mediated enhancement of profibrotic transcriptional signaling, suggesting that relatively higher SIRT4 expression may aggravate heart failure development in individuals with concomitant T2D.
2025-06-05 | GSE234210 | GEO
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2010-07-21 | E-GEOD-22778 | biostudies-arrayexpress
Project description:BackgroundWe recently reported that myeloid sirtuin 6 (Sirt6) is a critical determinant of phenotypic switching and the migratory responses of macrophages. Given the prominent role of macrophages in the pathogenesis of rheumatoid arthritis (RA), we tested whether myeloid Sirt6 deficiency affects the development and exacerbation of RA.MethodsArthritis was induced in wild type and myeloid Sirt6 knockout (mS6KO) mice using collagen-induced and K/BxN serum transfer models. Sirt6 expression (or activity) and inflammatory activities were compared in peripheral blood mononuclear cells (PBMCs) and monocytes/macrophages obtained from patients with RA or osteoarthritis.FindingsBased on clinical score, ankle thickness, pathology, and radiology, arthritis was more severe in mS6KO mice relative to wild type, with a greater accumulation of macrophages in the synovium. Consistent with these findings, myeloid Sirt6 deficiency increased the migration potential of macrophages toward synoviocyte-derived chemoattractants. Mechanistically, Sirt6 deficiency in macrophages caused an inflammation with increases in acetylation and protein stability of forkhead box protein O1. Conversely, ectopic overexpression of Sirt6 in knockout cells reduced the inflammatory responses. Lastly, PBMCs and monocytes/macrophages from RA patients exhibited lower expression of Sirt6 than those from patients with osteoarthritis, and their Sirt6 activity was inversely correlated with disease severity.InterpretationOur data identify a role of myeloid Sirt6 in clinical and experimental RA and suggest that myeloid Sirt6 may be an intriguing therapeutic target. FUND: Medical Research Center Program and Basic Science Research Program through the National Research Foundation of Korea.
| S-EPMC6306347 | biostudies-literature
Project description:Lee and colleagues demonstrate that sustained activation of AMPK enhances differentiation of iPSC-derived cardiomyocytes. Sustained AMPK activation decreased histone acetylation at known target sites for nuclear-localized sirtuins, suggesting that AMPK activation enhances sirtuin activity. AMPK-induced sirtuin-mediated deacetylation of histone proteins may regulate chromatin accessibility and enhance cardiomyocyte differentiation.
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Project description:We employed dermal fibroblasts isolated from Fgfr3G374Rneo+ mice, which do not express functional Fgfr3 (Fgfr3KO), from Fgfr3G374Rneo- mice with ligand-independent constitutive activation of Fgfr3 (Fgfr3Act) and from wildtype (WT) mice with normal expression of Fgfr3. Total RNA from these murine dermal fibroblasts (passage 4) were extracted and after quality control, were hybridized to the murine genome U74 gene chip. We have identified that Fgfr3 regulates important profibrotic pathways in fibroblasts. Selective upregulation of fibroblast growth factor receptor 3 (FGFR3) and its ligand FGF9 promote fibroblast activation and tissue fibrosis Transcriptome profiling, in silico analysis and functional experiments revealed that FGFR3 synergistically induces multiple profibrotic pathways including Endothelin-, Interleukin-4- and CTGF-signaling in a CREB-dependent manner. Inhibition of FGFR3 signaling by fibroblast-specific knockout of FGFR3 or FGF9 or pharmacological inhibition of FGFR3 inhibited fibroblast activation and attenuated experimental skin fibrosis. We have characterized FGFR3 as an upstream regulator of a network of profibrotic mediators and as a potential target for the treatment of fibrosis.
2020-10-01 | GSE148643 | GEO
Project description:Wollbold2014 - Effects of reactive oxygen
species
This model is described in the article:
Anti-inflammatory effects of
reactive oxygen species ¿ a multi-valued logical model
validated by formal concept analysis.
Wollbold J, Jaster R, Müller S,
Rateitschak K, Wolkenhauer O.
BMC Syst Biol 2014 Sep; 8(1): 101
Abstract:
BackgroundRecent findings suggest that in pancreatic acinar
cells stimulated with bile acid, a pro-apoptotic effect of
reactive oxygen species (ROS) dominates their effect on
necrosis and spreading of inflammation. The first effect
presumably occurs via cytochrome C release from the inner
mitochondrial membrane. A pro-necrotic effect ¿ similar to
the one of Ca2+ ¿ can be strong opening of mitochondrial
pores leading to breakdown of the membrane potential, ATP
depletion, sustained Ca2+ increase and premature activation of
digestive enzymes. To explain published data and to understand
ROS effects during the onset of acute pancreatitis, a model
using multi-valued logic is constructed. Formal concept
analysis (FCA) is used to validate the model against data as
well as to analyze and visualize rules that capture the
dynamics.ResultsSimulations for two different levels of bile
stimulation and for inhibition or addition of antioxidants
reproduce the qualitative behaviour shown in the experiments.
Based on reported differences of ROS production and of ROS
induced pore opening, the model predicts a more uniform
apoptosis/necrosis ratio for higher and lower bile stimulation
in liver cells than in pancreatic acinar cells. FCA confirms
that essential dynamical features of the data are captured by
the model. For instance, high necrosis always occurs together
with at least a medium level of apoptosis. At the same time,
FCA helps to reveal subtle differences between data and
simulations. The FCA visualization underlines the protective
role of ROS against necrosis.ConclusionsThe analysis of the
model demonstrates how ROS and decreased antioxidant levels
contribute to apoptosis. Studying the induction of necrosis via
a sustained Ca2+ increase, we implemented the commonly accepted
hypothesis of ATP depletion after strong bile stimulation.
Using an alternative model, we demonstrate that this process is
not necessary to generate the dynamics of the measured
variables. Opening of plasma membrane channels could also lead
to a prolonged increase of Ca2+ and to necrosis. Finally, the
analysis of the model suggests a direct experimental testing
for the model-based hypothesis of a self-enhancing cycle of
cytochrome C release and ROS production by interruption of the
mitochondrial electron transport chain.
This model is hosted on
BioModels Database
and identified by:
MODEL1407230001.
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2015-04-15 | MODEL1407230001 | BioModels
Project description:The role of sirtuin family in regulating DNA DSB repair has been extensively investigated, and here, we explore the molecular mechanisms of Sirtuin family in nucleotide excision repair.
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Project description:Phytochrome B regulates reactive oxygen signaling during stress in plants.
| PRJNA780007 | ENA