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Modulation of biological activities in adipose derived stem cells by histone deacetylation

ABSTRACT: Epigenetic mechanisms control stem cell homeostasis and differentiation as well as skin regeneration. In our study, we investigated the effects of Suberoylanilide hydroxamic acid (SAHA) on stem cells to understand the cellular and molecular impact. Adipose-derived stem cells received consecutive SAHA treatment for 72 hours. No change in the cell viability could be noticed at the studied concentrations. On the other hand, a decrease in the protein expression of histone deacetylases at 1000 nM was found. The cell proliferation marker (Ki-67) was increased after SAHA treatment compared to the vehicle as shown by immunofluorescence staining. The expression of CCND1 gene expression was upregulated, while the protein expression of the proliferating cell nuclear antigen was downregulated. Alternatively, microarray analysis revealed 74 up regulated and 40 downregulated differentially expressed genes and revealed that CDKN1A and MDM2 were upregulated under the influence of SAHA. On the other hand, the proteomics analysis identified 631 upregulated proteins while 823 proteins were downregulated in comparison to the vehicle. The pathway enrichment analysis showed that cell cycle, ATP-dependent chromatin remodeling and DNA are among the regulated pathways. This study suggested that SAHA as pharmaco-epigenetic agent might alter ADSCs determination through coordinated biological processes

ORGANISM(S): Homo sapiens

PROVIDER: GSE269774 | GEO | 2025/02/05

REPOSITORIES: GEO

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Project description:Heart Failure with preserved Ejection Fraction (HFpEF) is a major global health problem but there are no effective therapies. The aim of this study was to assess the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian (feline) pressure overload model with HFpEF features. Male domestic short hair cats (n=26, aged 2mo), underwent either a sham procedure (n=5) or aortic constriction (n=21) using a pre-shaped band, resulting in slow-progressive pressure overload during subsequent growth. Two-months post-banding, banded cats were treated daily with either 10mg/kg suberoylanilide hydroxamic acid (b+SAHA) (n=8), an FDA approved pan-HDAC inhibitor, or vehicle (b+veh) (n=8) for 2 months. Echocardiography at 4-months post-banding revealed that b+SAHA animals had a significant reduction in left ventricular hypertrophy (LVH) and LA size vs b+veh animals. Invasively measured left ventricular end-diastolic pressure (LVEDP) and mean pulmonary arterial pressure (mPAP) were significantly elevated in b+veh and significantly reduced by b+SAHA. SAHA speeded ex-vivo myofibril relaxation independent of LVH and this effect correlated with in-vivo indices of LV relaxation. Furthermore, SAHA preserved lung structure, improved lung compliance and oxygenation, reflected by a decrease in alveolar-capillary wall thickness, alveolar-arterial oxygen gradient (A-aDO2), and intrapulmonary shunt. SAHA also reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar-capillary stress failure. Acetylation proteomics revealed that SAHA altered protein acetylation in cat hearts, including histones, many mitochondrial metabolic enzymes involved in electron transport chain, TCA cycle, malate aspartate shuttle and beta oxidation, as well as cytoskeletal proteins important for muscle function. These results suggest that acetylation defects in hypertrophic stress states can be reversed by HDAC inhibitors and may be useful to improve cardiac structure and function in HFpEF patients.

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Modulation of biological activities in adipose derived stem cells by histone deacetylation

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