HDAC2 Regulates Glial Cell Activation in Ischemic Mouse Retina
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Abstract:
The current study was undertaken to investigate whether histone deacetylases (HDACs) can modulate the viability of retinal ganglion cells (RGCs) and the activity of glial cells in a mouse model of retinal ischemia-reperfusion (IR) injury. C57BL/6J mice were subjected to constant elevation of intraocular pressure for 60 min to induce retinal IR injury. Expression of macroglial and microglial cell markers (GFAP and Iba1), hypoxia inducing factor (HIF)-1α, and histone acetylation was analyzed after IR injury. To investigate the role of HDACs in the activation of glial cells, overexpression of HDAC1 and HDAC2 isoforms was performed. To determine the effect of HDAC inhibition on RGC survival, trichostatin-A (TSA, 2.5 mg/kg) was injected intraperitoneally. After IR injury, retinal GFAP, Iba1, and HIF-1α were upregulated. Conversely, retinal histone acetylation was downregulated. Notably, adenoviral-induced overexpression of HDAC2 enhanced glial activation following IR injury, whereas overexpression of HDAC1 did not significantly affect glial activation. TSA treatment significantly increased RGC survival after IR injury. Our results suggest that increased activity of HDAC2 is closely related to glial activation in a mouse model of retinal IR injury and inhibition of HDACs by TSA showed neuroprotective potential in retinas with IR injuries.Keywords:
Trichostatin A
Histone deacetylase 2
Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubicin-induced hypertrophy to examine the effects of the prototypical histone deacetylase inhibitor, Trichostatin A. Our findings indicate that doxorubicin modulates the expression of the hypertrophy-associated genes, ventricular myosin light chain-2, the alpha isoform of myosin heavy chain and atrial natriuretic peptide, an effect which is augmented by Trichostatin A. Furthermore, we show that Trichostatin A amplifies doxorubicin-induced DNA double strand breaks, as assessed by γH2AX formation. More generally, our findings highlight the importance of investigating potential side effects that may be associated with emerging combination therapies for cancer.
Trichostatin A
Cardiotoxicity
Histone deacetylase inhibitor
Histone deacetylase 5
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A series of new, structurally simple trichostatin A (TSA)-like straight chain hydroxamates were prepared and evaluated for their ability to inhibit partially purified human histone deacetylase 1 (HDAC-1). Some of these compounds such as 8m, 8n, 12, and 15b exhibited potent HDAC inhibitory activity with low nanomolar IC(50) values, comparable to natural TSA. These compounds induce hyperacetylation of histones in T24 human cancer cells and significantly inhibit proliferation in various human cancer cells. They also induce expression of p21 and cause cell cycle blocks in human cancer cells. In this paper, we describe the synthesis of these new compounds as well as structure-activity relationship results from enzyme inhibition and alterations in cellular function.
Trichostatin A
HDAC11
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Histone deacetylase 5
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Histone deacetylase (HDAC) inhibitors, such as trichostatin A and trapoxin, which were first found in microorganisms, potently and selectively inhibit HDAC enzymes. They have made a strong contribution to research on HDACs, chromatin control, abnormal epigenetic control in various diseases and the significance of acetylation in posttranslational modification. Recently, HDAC inhibitors have been focused on as potential drugs for the treatment of several diseases, including cancer, although trichostatin A and trapoxin show no effects in animal models because of their metabolic instability in vivo. Chemical modification has been conducted in order to overcome this drawback. We discovered the microbial metabolites FK228 (also known as FR901228, romidepsin, depsipeptide, NSC-630176 and NSC-630176D) and YM753 (spiruchostatin A). Both compounds have bicyclic structures and represent a novel structural class of HDAC inhibitor. The enzyme and tumor cell growth inhibitory activities of FK228 were found to be very potent. It also showed potent HDAC inhibitory activity in vivo. FK228 is the first potent HDAC inhibitor to undergo clinical development as a potential treatment for solid and hematological cancers. Due to its dramatic effect in patients with refractory cutaneous T-cell lymphoma (CTCL), in October 2004 the US Food & Drug Administration (FDA) granted fast-track status to FK228 as monotherapy for the treatment of CTCL in patients who have relapsed following, or become refractory to, another systemic therapy. Thus HDAC inhibitors such as FK228 and YM753 have potential as tools for life science studies and also as therapeutic agents for various intractable diseases.
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Depsipeptide
Trichostatin A
Histone deacetylase inhibitor
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Clinical importance of myocarditis, predominantly caused by coxsackievirus B3 (CVB3), is recently rising. However, a detailed mechanism of pathogenesis of CVB3 myocarditis still needs to be clarified. Recently, it has been reported that histone modifications including acetylation are involved in coxsackievirus replication. To examine whether the CVB3 replication requires histone acetylation, histone deacetylase (HDAC) inhibitors were employed. We found that the HDAC2 activity increased in virus-infected cells at 12 hrs p.i. and that HDAC inhibitors suppressed the virus replication in vitro. This suggests that the HDAC2 activity may be required for the virus replication. Eventually, a HDAC inhibitor trichostatin A protected against CVB3-induced myocardial injury in vivo. Our results suggest that HDAC may be a novel therapeutic target for treating viral myocarditis.coxsackievirus B3; histone acetyltransferase; histone deacetylase; HDAC inhibitors, trichostatin A; apicidin; valproic acid; shRNA; myocarditis; mouse.
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Histone acetyltransferase
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(R)-Trichostatin A (TSA) is a Streptomyces product which causes the induction of Friend cell differentiation and specific inhibition of the cell cycle of normal rat fibroblasts in the G1 and G2 phases at the very low concentrations. We found that TSA caused an accumulation of acetylated histone species in a variety of mammalian cell lines. Pulse-labeling experiments indicated that TSA markedly prolonged the in vivo half-life of the labile acetyl groups on histones in mouse mammary gland tumor cells, FM3A. The partially purified histone deacetylase from wild-type FM3A cells was effectively inhibited by TSA in a noncompetitive manner with Ki = 3.4 nM. A newly isolated mutant cell line of FM3A resistant to TSA did not show the accumulation of the acetylated histones in the presence of a higher concentration of TSA. The histone deacetylase preparation from the mutant showed decreased sensitivity to TSA (Ki = 31 nM, noncompetitive). These results clearly indicate that TSA is a potent and specific inhibitor of the histone deacetylase and that the in vivo effect of TSA on cell proliferation and differentiation can be attributed to the inhibition of the enzyme.
Trichostatin A
Histone deacetylase inhibitor
HDAC11
Histone deacetylase 5
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Histone deacetylase (HDAC) inhibitors are promising antitumoral drugs. Currently there are no data regarding the comparison of different HDAC inhibitors on hepatoma cells.Hepatoma cells were incubated with the HDAC inhibitors MS-275, SAHA, FK901228 and trichostatin. Proliferation was assessed via BrdU incorporation and apoptosis rate via flow cytometry. Trichostatin, SAHA and MS-275 were applied in a rat hepatoma model.The agents showed antiproliferative and pro-apoptotic effects time- and dose-dependently. SAHA and MS-275 were moderately effective at 10 μM, while trichostatin A and FK901228 showed higher potency. Caspases 3 and 8 were activated upon treatment with the drugs. The agents increased the acetylation rate. Hyperacetylation did not correlate with antitumoral efficacy. In vivo, SAHA was superior to MS-275 and trichostatin A.The HDAC inhibitors were effective both in vitro and in vivo. The potency of SAHA and MS-275 was similar. In spite of differing affinity to the 11 known HDACs, the agents induced comparable effects. These findings suggest that these agents have further antitumoral effects apart from HDAC inhibition.
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Inhibitors of histone deacetylase are attracting increasing interest due to their influence on transcription, differentiation, and apoptosis. We have investigated two synthetic inhibitors 3 and 4 of histone deacetylase and the natural product inhibitor trichostatin A for their ability to suppress the growth of MCF-7 breast cancer cells and here present complete and improved synthetic procedures. The compounds show a dose dependent inhibition of growth with activities in the low micromolar and nanomolar range. Trichostatin shows cytocidal effects at 100 nM and still has activity comparable to cisplatin (0.5 μM) at 10 nM. Whereas the synthetic inhibitor 3 has cytocidal activity at 10 μM compound 4 shows a maximum of 40% growth suppression at that concentration.
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Histone deacetylase inhibitor
MCF-7
Growth inhibition
HDAC11
Histone deacetylase 5
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Histone deacetylase inhibitors (HDACi) are increasingly used as therapeutic agents, but the mechanisms by which they alter cell behaviour remain unclear. Here we use microarray expression analysis to show that only a small proportion of genes (∼9%) have altered transcript levels after treating HL60 cells with different HDACi (valproic acid, Trichostatin A, suberoylanilide hydroxamic acid). Different gene populations respond to each inhibitor, with as many genes down- as up-regulated. Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated. Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi.
Trichostatin A
HDAC11
Vorinostat
Histone deacetylase 2
Histone deacetylase inhibitor
Histone deacetylase 5
HDAC4
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Objective
To investigate the effects of trichostatin (TSA) on neonatal rat cardiomyocyte hypertrophy induced by angiotensin Ⅱ (AngⅡ) infusion.
Methods
Primary cultured neonatal rat cardiomyocytes were treated with angiotensin Ⅱ with or in the absence of TSA pretreatment. Cardiomyocytes cross area, [3H] Leucine incorporation rate, as well as mRNA expression level of ANP and BNP, were measured. The protein expression level of acetylated histone H3 and phosphorylated JNK was also examined.
Results
The cardiomyocyte cross area enlarged to (1.63±0.46) times to the original, which was blunted by pretreatment of TSA at the dosage of 10-7 mmol/L and 3×10-7 mmol/L. Increased protein synthesis rates and upregulation of mRNA expression of ANP as well as BNP by AngⅡ stimulation, were also blocked by TSA treatment. The protein expressions of acetylated histone H3, as well as phosphorylated JNK were upregulated by AngⅡ induction, which were also inhibited by TSA.
Conclusions
TSA pretreatment blunts cardiomyocyte hypertrophy induced by Ang Ⅱ infusion, which is possibly due to the inhibition of total histone deacetylase (HDAC) activity and JNK activation.
Key words:
Heart failure; Histone deacetylase inhibitors; Histone deacetylases; Trichostatin
Trichostatin A
Histone deacetylase 2
Histone deacetylase 5
HDAC4
Histone deacetylase inhibitor
HDAC11
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Trichostatin A
Histone deacetylase inhibitor
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