Inhibition of histone deacetylase on ventricular remodeling in infarcted rats

2007 ◽  
Vol 293 (2) ◽  
pp. H968-H977 ◽  
Author(s):  
Tsung-Ming Lee ◽  
Mei-Shu Lin ◽  
Nen-Chung Chang
Keyword(s):  
Histone Deacetylase ◽  
Ventricular Remodeling ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Left Ventricular ◽  
Border Zone ◽  
Cardiomyocyte Hypertrophy ◽  
Collagen Formation

Histone deacetylase (HDAC) determines the acetylation status of histones and, thereby, controls the regulation of gene expression. HDAC inhibitors have been shown to inhibit cardiomyocyte growth in vitro and in vivo. We assessed whether HDAC inhibitors exert a beneficial effect on the remodeling heart in infarcted rats. At 24 h after ligation of the left anterior descending artery, male Wistar rats were randomized to vehicle, HDAC inhibitors [valproic acid (VPA) and tributyrin], an agonist of HDAC (theophylline), VPA + theophylline, or tributyrin + theophylline for 4 wk. Significant ventricular hypertrophy was detected as increased myocyte size at the border zone isolated by enzymatic dissociation after infarction. Cardiomyocyte hypertrophy and collagen formation at the remote region and border zone were significantly attenuated by VPA and tributyrin with a similar potency compared with that induced by the vehicle. Left ventricular shortening fraction was significantly higher in the VPA- and tributyrin-treated groups than in the vehicle-treated group. Increased synthesis of atrial natriuretic peptide mRNA after infarction was confirmed by RT-PCR, consistent with the results of immunohistochemistry and Western blot for acetyl histone H4. The beneficial effects of VPA and tributyrin were abolished by theophylline, implicating HDAC as the relevant target. Inhibition of HDAC by VPA or tributyrin can attenuate ventricular remodeling after infarction. This might provide a worthwhile therapeutic target.

scholarly journals Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

2012 ◽  
Vol 56 (7) ◽  
pp. 3849-3856 ◽  
Author(s):  
Subathdrage D. M. Sumanadasa ◽  
Christopher D. Goodman ◽  
Andrew J. Lucke ◽  
Tina Skinner-Adams ◽  
Ishani Sahama ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Antimalarial Activity ◽  
Hdac Inhibitors ◽  
Parasite Life Cycle ◽  
Nonhistone Proteins ◽  
Content Type

ABSTRACTHistone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, thein vitroandin vivoantiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth ofPlasmodium falciparumasexual-stage parasitesin vitro(50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited thein vitrogrowth of exoerythrocytic-stagePlasmodiumparasites in liver cells (IC50, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimentalin vivomurine model of cerebral malaria, orally administered SB939 significantly inhibitedP. bergheiANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.

Downregulation of Graft-Versus-Host-Disease (GVHD) by Treatment with Histone Deacetylase (HDAC) Inhibitors Involves Modulation of the JAK/STAT Signaling Pathway.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3050-3050
Author(s):  
Corinna Leng ◽  
Margathe Gries ◽  
Suzanne Lentzsch ◽  
Simone Lusatis ◽  
Paolo Mascagni ◽  
...  
Keyword(s):  
T Cell ◽  
Histone Deacetylase ◽  
Graft Versus Host Disease ◽  
Hdac Inhibitors ◽  
Inhibitory Effect ◽  
Graft Versus Host ◽  
Stat Signaling ◽  
Stat Pathway

Abstract Graft-versus-host disease (GVHD) mediated by alloreactive donor T cells is the most dreaded complication after allogeneic bone marrow transplantation (BMT). Conditioning therapy in the context of BMT creates a proinflammatory milieu, which is thought to be central to the development of GVHD. Interfering with the conditioning-induced inflammatory response could be an approach to prevent GVHD without compromising the graft-versus-malignancy reaction. Histone deacetylase (HDAC) inhibitors belong to a new family of anti-cancer drugs with potent anti-inflammatory properties and have recently been shown to reduce the development of GVHD. The aim of this study was understand the mechanisms underlying the downregulation of GVHD after treatment with the HDAC inhibitor suberonylanilide hydroxamic acid (SAHA). Using the fully MHC-mismatched strain combination B6 to BALB/c, treatment with SAHA resulted in a significantly reduced GVHD mortality. Thus, at days +10 or +37 post-BMT survival for vehicle-treated or SAHA-treated mice was 33 % versus 86 % and 8 % versus 57 % respectively (Chi2 test, p = 0,027 and p = 0,02, respectively). This was associated with a significant reduction in IFN-g and IL-5 serum levels of SAHA-treated animals. As we could not detect any effect of SAHA treatment on T cell activation or T cell expansion in vitro and in vivo, we hypothesized that the inhibitory effect of SAHA treatment on the development of GVHD might be primarily due to an interference in the early events of the inflammatory cascade occurring after conditioning and initial alloactivation. Therefore, we performed gene expression profiling studies in classical GVHD target organs of animals treated with SAHA or vehicle to further understand the mechanisms underlying this effect. SAHA treated animals revealed a significant upregulation of the mRNA expression of the Protein inhibitor of activated stat 1 (PIAS1) gene in the liver compared to vehicle-treated animals. To further strengthen the hypothesis that SAHA might exert its action by interfering with inflammatory reaction and subsequent signaling through the JAK/STAT pathway, we analyzed the effects of SAHA on STAT-1, 3, and 5 activation and expression of SOCS-1 and SOCS-3 in vitro and in vivo. Thus, BALB/c responder splenocytes were incubated with or without irradiated B6 stimulators in the presence or absence of LPS in order to allow for the separate analysis of LPS and alloactivation-induced JAK/STAT activation. Treatment for 24 hours with SAHA completely inhibited phosphorylation of STAT-1 and STAT-3 in response to LPS and alloactivation using western blot analysis. Furthermore, analysis of liver tissue from GVHD animals showed a sustained expression of SOCS-1 protein in SAHA treated animals whereas SOCS-1 was downregulated in the absence of SAHA. In conclusion our data suggest that the inhibitory effect of SAHA on the development of GVHD is associated with an inhibition of the JAK/STAT signaling pathway. Further studies are warranted to understand the precise mechanisms how SAHA interferes with JAK/STAT signaling and how this leads to inhibition of GVHD. However, it is conceivable that interfering with inflammatory signaling pathways using pharmacological inhibitors of the JAK/STAT pathway might provide a highly attractive treatment strategy for the prevention of GVHD.

Potent Induction of Human γ Globin Gene Expression by Largazole, a New Histone Deacetylase Inhibitor.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2022-2022
Author(s):  
Hua Cao ◽  
Rui Gao Fei ◽  
Albert A. Bowers ◽  
Thomas J. Greshock ◽  
Tenaya Newkirt ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Globin Gene ◽  
Control Level ◽  
Hdac Inhibitors ◽  
Fetal Hemoglobin ◽  
Vitro Effect

Abstract Abstract 2022 Poster Board I-1044 Previous studies have demonstrated that Histone Deacetylase (HDAC) inhibitors such as butyrate and several short chain fatty acids, can induce fetal hemoglobin in humans and animal models; however induction of Hb F is achieved in relatively high concentrations of these compounds. We have previously investigated the induction of human γ globin gene activity by the prototypical HDAC inhibitor, FK228. The results demonstrated that FK228 is a more potent γ globin gene inducer compared to other HDAC inhibitors we have tested before (Am J Hematol. 12:981). In this study, we investigated the induction of human γ globin gene function of largazole and it's thiol analogue in vitro in cultures of normal human adult BFUe and in vivo in the mice carrying a human γ globin transgene. Largazole is a HDAC inhibitor which was recently isolated from a marine vyanobacterium by Luesch and co-workers. Structural features of largazole, a macrocyclic depsopeptide, closely resemble those of FK228, FR901375 and spiruchostatin. We have reported that largazole and numerous synthetic analogues are highly potent Class I histone deacetylase inhibitors (J Am Chem Soc. 130:11219, J Am Chem Soc. 2009 Feb 4). We used flow cytometry to measure the in vitro effect of largazole and it's derivatives on the frequency of HbF-positive erythroblasts in BFUe cultures from normal individuals; real-time quantitative PCR (RT-qPCR) and high performance liquid chromatography (HPLC) were used to measure the in vivo effects of largazole on human γ globin induction in γ transgenic mice carrying a human γ globin gene.. Our results show that largazole and it's thiol derivative are potent γ hemoglobin gene inducers. In the human BFUe cultures, largazole increased the levels of fetal hemoglobin positive cells from 21.9% (control level) to 62.8% at a concentration of 0.1μM; largazole thiol increased the levels of fetal hemoglobin positive cells to 62.0% at a concentration of 1μM. Transgenic mice carrying the human μLCR Aγ construct continue to express the human γ gene in the adult stage (Blood. 77:1326). Largazole was administered through IP injection at the dosages of 0.3mg/kg/day and 0.6mg/kg/day, 5 days per week, for 2 weeks to two cohorts of transgenic mice. Largazole at the dose of 0.3mg/kg/day increased the level of human γ mRNA at the end of injection by 160.7%; at a dose of 0.6mg/kg/day human γ mRNA increased by 174.7%. At the 0.6mg/kg/day dosage the level of fetal hemoglobin in the peripheral blood of the animals increased by 3.4 and 3.2 fold at day 21 and day 28, respectively. These results provide strong in vitro and in vivo evidence that Largazole and it's thiol analogue are potent HbF inducers acting at low concentrations, and thus provide promising alternatives to compounds currently considered for induction of Hb F in patients with sickle cell disease and thalassemia. Disclosures: No relevant conflicts of interest to declare.

NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2615-2622 ◽  
Author(s):  
Laurence Catley ◽  
Ellen Weisberg ◽  
Yu-Tzu Tai ◽  
Peter Atadja ◽  
Stacy Remiszewski ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Histone Deacetylase ◽  
Hdac Inhibitors ◽  
Myeloma Cell ◽  
Parp Cleavage ◽  
Significant Activity ◽  
Dependent Manner

Abstract Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM. (Blood. 2003;102:2615-2622)

scholarly journals Low‐intensity Pulsed Ultrasound Ameliorates Angiotension Ii-induced Cardiac Fibrosisbyalleviating Inflammation via a Caveolin-1-dependent Pathway

2020 ◽  
Author(s):  
Kun Zhao ◽  
Jing Zhang ◽  
Tianhua Xu ◽  
Chuanxi Yang ◽  
Liqing Weng ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Pulsed Ultrasound ◽  
Caveolin 1 ◽  
Low Intensity Pulsed Ultrasound

Abstract Background: Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by Angiotensin II (AngII). Concerning the fact that low‐intensity pulsed ultrasound (LIPUS) has been reported to improve cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechanotransductionanditsdownstream pathways, we aimed to investigate whether LIPUS could also exert a protective effect on ameliorating AngII-induced cardiac hypertrophy and fibrosis andand if so, to further elucidate the underlying molecular mechanisms.Methods: In our study, we used AngII to mimic the animal and cell culture models of cardiac hypertrophy and fibrosis, where LIPUS irradiation (0.5MHz, 77.20mW/cm2) was applied for 20 minutes every 2 days from 1 week before surgery to 4 weeks after surgery in vivo, and every 6 hours for a total of 2 times in vitro. Following that, the levels of cardiac hypertrophy and fibrosis were evaluated by echocardiographic, histopathological, and molecular biological methods. Results: Our results showed that LIPUS irradiation could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-inducedrelease of inflammatory cytokines, while the protective effects were limited on cardiac hypertrophy in vitro. Given that LIPUS irradiation increased the expression of caveolin-1 related to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vitro, by which LIPUS-induced downregulation of inflammation was reversed and the anti-fibrosis effects of LIPUS irradiation were absent. Conclusions: Taken together, these results indicate that LIPUS irradiation could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeuticapparatus in clinical practice.

Abstract 16434: IL-6 Signaling is Crucial for Cardiomyocyte Hypertrophy and Left Ventricular Dysfunction Induced by Pressure Overload

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Lin Zhao ◽  
Guangming Cheng ◽  
Yanjuan Yang ◽  
Anweshan Samanta ◽  
Rizwan R Afzal ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Function ◽  
Ang Ii ◽  
Adult Cardiomyocytes

Introduction: Interleukin-6 (IL-6), a proinflammatory cytokine, has been implicated in ischemic cardiac pathologies. Very little is currently known regarding the role of IL-6 signaling in pathological cardiomyocyte hypertrophy and LV dysfunction. Hypothesis: We hypothesized that IL-6 signaling plays a central role in cardiomyocyte hypertrophy and exerts a deleterious impact on LV remodeling induced by pressure overload. Methods: In vitro, adult cardiomyocytes from C57BL/6 (WT, control) and IL-6 knockout (KO) mice were stimulated by IL-6 and pro-hypertrophic agent angiotensin II (Ang II). The expression of hypertrophy markers and related signaling molecules were examined by real-time quantitative RT-PCR. In vivo, weight-matched male WT and IL-6 KO mice underwent transverse aortic constriction (TAC) or a sham procedure. Serial echocardiograms and a terminal hemodynamic study were performed. Results: After exposure to IL-6 and hypertrophic agonists, the expression of hypertrophy related genes, BNP, GATA-4, αSK actin, and β-MHC increased significantly in WT cardiomyocytes (Fig). These effects were significantly attenuated in IL-6 knockout cardiomyocytes (Fig), indicating an essential role of IL-6 in cardiomyocyte hypertrophy. In vivo, the worsening in LV contraction as well as relaxation after TAC was significantly attenuated in IL-6 KO mice, indicating superior preservation of LV function in the setting of pressure overload in the absence of IL-6 signaling. Conclusions: The protection against Ang II-induced hypertrophy observed in IL-6 KO adult cardiomyocytes in vitro, and in hearts of IL-6 KO mice after TAC in vivo illustrates a crucial role played by IL-6 in pathogenesis of pressure overload-induced LV hypertrophy. Modulation of IL-6 signaling may have preventive therapeutic potential for countless hypertensive patients at risk for LV hypertrophy and failure.

The Novel Histone Deacetylase Inhibitor OSU-HDAC42 Has Class I and II Histone Deacetylase (HDAC) Inhibitory Activity and Represents a Novel Therapy for Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2807-2807
Author(s):  
Derek A. West ◽  
David M. Lucas ◽  
Melanie E. Davis ◽  
Michael D. De Lay ◽  
Amy J. Johnson ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Histone Deacetylase ◽  
Inhibitory Activity ◽  
Hdac Inhibitors ◽  
Clinical Development ◽  
Lymphocytic Leukemia ◽  
In Vivo Efficacy

Abstract Inhibitors of histone deacetylase (HDAC) have generated major interest for the treatment of multiple cancers including B-cell Chronic Lymphocytic Leukemia (CLL). To date, HDAC inhibitors introduced for clinical development in CLL have been associated either with suboptimal activity relative to concentrations required to mediate cytotoxicity in vitro (Valproic Acid, MS-275, SAHA), or demonstrate unacceptable acute or long-term toxicities (depsipeptide) that limit their clinical potential. Fortunately, several alternative HDAC inhibitors are in pre-clinical or early clinical development. One such agent currently undergoing pre-clinical testing by the National Cancer Institute-sponsored RAID program is OSU-HDAC42 (s-HDAC-42), a novel, orally bioavailable phenylbutyrate-derived HDAC inhibitor with both in vitro and in vivo efficacy against prostate cancer cells. We therefore tested OSU-HDAC42 against CD19-positive cells obtained from patients with CLL to determine its potential in this disease. The LC50 of OSU-HDAC42 in CLL cells was 0.46 uM at 48 hours of continuous incubation by MTT assay, which was corroborated by annexin V-FITC/propidium iodide flow cytometry. To determine the minimum amount of time that OSU-HDAC42 must be present to induce cell death, cells were incubated for various times, washed, resuspended in fresh media without drug, then assessed by MTT at a total of 48 hours incubation. The effects of OSU-HDAC42 were eliminated in CLL cells when drug was removed after 4 or 6 hours. However, there was a gradual increase in effect over time, and by 16 hours, approximately 60% of the cytotoxicity achieved with continuous incubation was retained. OSU-HDAC42 induced acetylation of histone proteins H3 and H4 as early as 4 hours that was dose and time dependent. LC/MS interrogation of OSU-HDAC42-treated CLL cells is currently underway to determine specific post-translational modification changes of all histone proteins and variants. OSU-HDAC42 also was able to sensitize CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL) at 24 hours in a dose-dependent manner, supporting its class I HDAC inhibitory activity as recently reported by Inoue and colleagues (Cancer Res.2006; 66:6785). Evidence of class II HDAC inhibitory activity was also observed with OSU-HDAC42 at 12 hours with acetylation of tubulin. Unlike depsipeptide, OSU-HDAC42 activated both caspase-8 and -9 followed by PARP processing. Cell death induced by OSU-HDAC42 was completely inhibited with pre-treatment by the pan-caspase inhibitor Z-VAD-FMK. In vivo experiments are underway to examine the efficacy of OSU-HDAC42 in several murine models of leukemia to confirm in vivo efficacy as well as influence on murine effector cells. Our data strongly support continued investigation of OSU-HDAC42 in CLL and related B-cell malignancies.

Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo

2009 ◽  
Vol 36 (2) ◽  
pp. 269-279 ◽  
Author(s):  
Giuseppe Faraco ◽  
Maria Pittelli ◽  
Leonardo Cavone ◽  
Silvia Fossati ◽  
Marco Porcu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Histone Deacetylase ◽  
Hdac Inhibitors

Additive effects of combined blockade of AT1 receptor and HMG-CoA reductase on left ventricular remodeling in infarcted rats

2006 ◽  
Vol 291 (3) ◽  
pp. H1281-H1289 ◽  
Author(s):  
Tsung-Ming Lee ◽  
Mei-Shu Lin ◽  
Tsai-Fwu Chou ◽  
Nen-Chung Chang
Keyword(s):  
Myocardial Infarction ◽  
Combination Treatment ◽  
Ventricular Remodeling ◽  
Left Ventricular ◽  
Border Zone ◽  
Cardiomyocyte Hypertrophy ◽  
Angiotensin Receptor ◽  
Hmg Coa Reductase ◽  
Endothelin 1 ◽  
Coa Reductase

Both angiotensin receptor antagonists and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to attenuate cardiomyocyte hypertrophy after myocardial infarction. Whether combination treatment may be superior to either drug alone on cardiomyocyte hypertrophy remains unclear. After ligation of the left anterior descending artery, rats were randomized to both, one, or neither of the angiotensin receptor antagonists olmesartan (0.01, 0.1, 1, and 2 mg·kg−1·day−1) and HMG-CoA reductase inhibitor pravastatin (5 mg·kg−1·day−1) for 4 wk. Each drug, when given alone, decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone when compared with vehicles. However, compared with either drug alone, combined olmesartan and pravastatin prevent cardiomyocyte hypertrophy to a larger extent, which was further confirmed by downregulation of the left ventricular atrial natriuretic peptide mRNA. The myocardial endothelin-1 levels at the border zone were 6.5-fold higher ( P <0.0001) in the vehicle group compared with the sham group, which can be inhibited after pravastatin administration. Combination treatment significantly attenuated cardiomyocyte hypertrophy in a dose-dependent manner, although tissue endothelin-1 levels remained stable in combination groups of different olmesartan doses. Measurements of the arrhythmic score mirrored those of cardiomyocyte hypertrophy. Dual therapy with pravastatin and olmesartan, which produced an additive reduction in cardiomyocyte hypertrophy and cardiac fibrosis after myocardial infarction through different mechanisms, decreases the propensity of the heart to arrhythmogenesis. Pravastatin administration provided favorable ventricular remodeling, probably through decreased tissue endothelin-1 level. In contrast, olmesartan-related attenuated cardiomyocyte hypertrophy is independent of endothelin-1 pathway.

scholarly journals Improved development of mouse SCNT embryos by chlamydocin analogues, class I and IIa histone deacetylase inhibitors†

2021 ◽  
Author(s):  
Satoshi Kamimura ◽  
Kimiko Inoue ◽  
Eiji Mizutani ◽  
Jin-Moon Kim ◽  
Hiroki Inoue ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Class I ◽  
Cell Stage ◽  
Inhibitory Spectrum ◽  
Developmental Block

Abstract In mammalian cloning by somatic cell nuclear transfer (SCNT), treatment of reconstructed embryos with histone deacetylase (HDAC) inhibitors improves efficiency. So far, most of those used for SCNT are hydroxamic acid derivatives—such as trichostatin A—characterized by their broad inhibitory spectrum. Here, we examined whether mouse SCNT efficiency could be improved using chlamydocin analogues, a family of newly designed agents that specifically inhibit Class I and IIa HDACs. Development of SCNT-derived embryos in vitro and in vivo revealed that four out of five chlamydocin analogues tested could promote the development of cloned embryos. The highest pup rates (7.1 to 7.2%) were obtained with Ky-9, similar to those achieved with trichostatin A (7.2 to 7.3%). Thus, inhibition of Class I and/or IIa HDACs in SCNT-derived embryos is enough for significant improvements in full-term development. In mouse SCNT, the exposure of reconstructed oocytes to HDAC inhibitors is limited to 8–10 h because longer inhibition with Class I inhibitors causes a 2-cell developmental block. Therefore, we used Ky-29, with higher selectivity for Class IIa than Class I HDACs for longer treatment of SCNT-derived embryos. As expected, 24-h treatment with Ky-29 up to the 2-cell stage did not induce a developmental block, but the pup rate was not improved. This suggests that the 1-cell stage is a critical period for improving SCNT cloning using HDAC inhibitors. Thus, chlamydocin analogues appear promising for understanding and improving the epigenetic status of mammalian SCNT-derived embryos through their specific inhibitory effects on HDACs.

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