Objective To investigate the expression levels of class Ⅰ histone deacetylases(HDAC)in the serum of patients with newly diagnosed psoriatic arthritis(PsA)and screen out serological indicators that are of significance for early diagnosis and assessment of disease activity.Methods A total of 49 PsA patients newly diagnosed in Shanxi Provincial People's Hospital from August 2022 to February 2024 and 30 healthy individuals(control group)were enrolled in this study.Demographic data were collected,and disease severity was assessed.Serum samples were collected,and the expression levels of class Ⅰ HDAC(HDAC1,HDAC2,HDAC3,and HDAC8)in the serum of each group were determined by ELISA.The correlations between the expression levels of class Ⅰ HDAC and clinical assessment indicators in each group were evaluated.Multivariate Logistic regression was adopted to analyze the risk factors affecting the disease activity of PsA patients.The receiver operating characteristic curve was used to evaluate the diagnostic efficacy of the risk factors affecting the disease activity of PsA patients.Results Compared with the control group,PsA patients showed up-regulated expression levels of HDAC1(P=0.003),HDAC2(P=0.010),HDAC3(P=0.003),and HDAC8(P=0.018)in the serum.The serum HDAC1 level of PsA patients was positively correlated with erythrocyte sedimentation rate(r=0.344,P=0.028).The serum HDAC2 level was positively correlated with the overall assessment of disease activity(r=0.468,P=0.001),the disease activity index of arthritis(r=0.401,P=0.007),the number of swollen joints(r=0.308,P=0.042),hospital anxiety and depression scale(HADS)score of anxiety(r=0.360,P=0.018),and HADS score of depression(r=0.302,P=0.047).The serum HDAC3 level was correlated with erythrocyte sedimentation rate(r=0.542,P<0.001),C-reactive protein(CRP)level(r=0.440,P<0.001),HADS score of anxiety(r=0.420,P=0.005),interleukin-6 level(r=0.397,P=0.004),the overall assessment of disease activity(r=0.318,P=0.036),and the course of psoriatic arthritis(r=0.330,P=0.028).The serum HDAC8 level was positively correlated with HADS score of anxiety(r=0.477,P=0.008)and erythrocyte sedimentation rate(r=0.385,P=0.039).Compared with the patients with low disease activity,those with moderate to high disease activity presented up-regulated expression of HDAC3(P=0.041).HDAC2(P=0.028)and CRP(P=0.034)were risk factors for moderate to high disease activity in PsA patients.HDAC2(area under the curve=0.802,P=0.003)and CRP(area under the curve=0.718,P=0.033)had diagnostic value for the progression of PsA.Conclusions The expression levels of class Ⅰ HDAC in the serum of patients with newly diagnosed PsA were significantly different.The serum levels of HDAC2 and CRP are expected to become serological indicators for the early diagnosis and disease activity assessment of PsA.
Humans ; Histone Deacetylases/blood* ; Arthritis, Psoriatic/diagnosis* ; Male ; Female ; Histone Deacetylase 1/blood* ; Histone Deacetylase 2/blood* ; Adult ; Middle Aged ; Clinical Relevance ; Repressor Proteins

BACKGROUND AND OBJECTIVES: Dysregulation of histone deacetylase expression and enzymatic activity is associated with a number of diseases. It has been reported that protein levels of histone deacetylase (HDAC)1 and HDAC5 increase during human pulmonary hypertension, and that the enzymatic activity of HDAC6 is induced in a chronic hypertensive animal model. This study investigated the protein expression profiles of class I and II a/b HDACs in three systemic hypertension models. SUBJECTS AND METHODS: We used three different hypertensive animal models: (i) Wistar-Kyoto rats (n=8) and spontaneously hypertensive rats (SHR; n=8), (ii) mice infused with saline or angiotensin II to induce hypertension, via osmotic mini-pump for 2 weeks, and (iii) mice that were allowed to drink L-N(G)-nitro-L-arginine methyl ester (L-NAME) to induce hypertension. RESULTS: SHR showed high systolic, diastolic, and mean blood pressures. Similar increases in systolic blood pressure were observed in angiotensin II or L-NAME-induced hypertensive mice. In SHR, class IIa HDAC (HDAC4, 5, and 7) and class IIb HDAC (HDAC6 and 10) protein expression were significantly increased. In addition, a HDAC3 protein expression was induced in SHR. However, in L-NAME mice, class IIa HDAC protein levels (HDAC4, 5, 7, and 9) were significantly reduced. HDAC8 protein levels were significantly reduced both in angiotensin II mice and in SHR. CONCLUSION: These results indicate that dysregulation of class I and class II HDAC protein is closely associated with chronic hypertension.
Angiotensin II ; Animals* ; Blood Pressure ; Histone Deacetylases* ; Histones* ; Humans ; Hypertension ; Hypertension, Pulmonary ; Mice ; Models, Animal* ; NG-Nitroarginine Methyl Ester ; Rats ; Rats, Inbred SHR

CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.
Animals ; Blood Pressure ; Body Weight ; Cardiomegaly* ; Chemistry ; Cholesterol ; Connective Tissue Growth Factor ; Desoxycorticosterone ; Desoxycorticosterone Acetate ; Drinking Water ; Eosine Yellowish-(YS) ; Fibronectins ; Fibrosis* ; Glucose ; Heart ; Hematoxylin ; Histone Deacetylase Inhibitors* ; Histone Deacetylases* ; Histones* ; Hypertension ; Methods ; Potassium ; Rats* ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Relaxation ; Sodium ; Triglycerides

OBJECTIVETo evaluate the roles of various cytokines, histone acetyltransferase (HAT) and histone deacetylase (HDAC) in the pathogenesis of bronchial asthma.

METHODSBALB/C mice were randomly assigned to control, untreated asthma, hormone treatment and TSA treatment groups. Bronchial asthma was induced by intraperitoneal injections and atomization inhalation of ovalbumin (OVA) in the asthma, hormone treatment and trichostatin (TSA) treatment groups. The mice in the hormone treatment and TSA treatment groups were administered with dexamethasone 1.0 mg/kg and TSA 1.0 mg/kg respectively by an intraperitoneal injection 30 minutes before challenge of asthma. At 24 hours after the last challenge, IL-4, IL-8 and IFN- levels in serum were measured using ELISA, and activities of HAT and HDAC in peripheral blood mononuclear cells (PBMC) were determined by the enzyme linked immunofluorescence assay.

RESULTSThe serum levels of IL-4 and IL-8 in the untreated asthma group were higher than in the control, hormone treatment and TSA treatment groups (P<0.05). There was no difference in the serum levels of IL-4 and IL-8 among the control, hormone treatment and TSA treatment groups (P>0.05). The activity of HDAC in the untreated asthma group was lower than in the control, hormone treatment and TSA treatment groups (P<0.05). Hormone treatment significantly decreased the activity of HAT compared with the untreated asthma group (P<0.05). There was no difference in the activities of HAT and HDAC among the control, hormone treatment and TSA treatment groups (P>0.05).

CONCLUSIONSThe decreased activity of HDAC leads to an increased secretion of inflammatory factors and thus induces asthma.

Animals ; Asthma ; enzymology ; etiology ; immunology ; Cytokines ; blood ; Histone Acetyltransferases ; physiology ; Histone Deacetylases ; physiology ; Male ; Mice ; Mice, Inbred BALB C ; Th1 Cells ; immunology ; Th2 Cells ; immunology

Histone deacetylase (HDAC) has been recognized as a potentially useful therapeutic target for cardiovascular disorders. However, the effect of the HDAC inhibitor, trichostatin A (TSA), on vasoreactivity and hypertension remains unknown. We performed aortic coarctation at the inter-renal level in rats in order to create a hypertensive rat model. Hypertension induced by abdominal aortic coarctation was significantly suppressed by chronic treatment with TSA (0.5 mg/kg/day for 7 days). Nicotinamide adenine dinucleotide phosphate-driven reactive oxygen species production was also reduced in the aortas of TSA-treated aortic coarctation rats. The vasoconstriction induced by angiotensin II (Ang II, 100 nM) was inhibited by TSA in both endothelium-intact and endothelium-denuded rat aortas, suggesting that TSA has mainly acted in vascular smooth muscle cells (VSMCs). In cultured rat aortic VSMCs, Ang II increased p66shc phosphorylation, which was inhibited by the Ang II receptor type I (AT1R) inhibitor, valsartan (10 microM), but not by the AT2R inhibitor, PD123319. TSA (1~10 microM) inhibited Ang II-induced p66shc phosphorylation in VSMCs and in HEK293T cells expressing AT1R. Taken together, these results suggest that TSA treatment inhibited vasoconstriction and hypertension via inhibition of Ang II-induced phosphorylation of p66shc through AT1R.
Angiotensin II ; Angiotensins* ; Animals ; Aorta ; Aortic Coarctation ; Blood Pressure* ; Histone Deacetylases ; Hypertension ; Models, Animal ; Muscle, Smooth, Vascular ; NAD ; Phosphorylation ; Rats ; Reactive Oxygen Species ; Vasoconstriction* ; Valsartan

OBJECTIVE: To evaluate therapeutic eff ect of siRNA-HDAC5 on non-obese diabetic (NOD) mice by using small interference RNA (siRNA) technique to knock down the expression of HDAC5 in spleen CD4+ T cells. METHODS: NOD mice, 12-weeks old, were randomly divided into 3 groups and were given normal saline, siRNA-Control or siRNA-HDAC5 through caudal vein injection. The spleens and other samples were collected at the 18th, 24th or 30th week. The blood glucose was tested by blood glucose meter. The urinary albumin and serum levels of IL-1, IL-6, IL-18, and TNF-α were detected by ELISA. The mRNA levels of CD11a, CCR5, and CX3CR1 in spleen CD4+ T cells were measured by quantitative Real-time PCR. The HDAC5 protein level in spleen CD4+ T cell was detected by Western blot. RESULTS: Compared with the control group, the siRNA-HDAC5 group showed a significant decrease in blood glucose, urine albumin excretion rate, serum cytokine and the mRNA levels of CD11a, CCR5, and CX3CR1, consist with the decrease in protein level of HDAC5. CONCLUSION Inhibition of HDAC5 expression in NOD mice could effectively alleviate the onset and development of kidney damage caused by diabetes.
Animals ; CD11a Antigen ; metabolism ; CD4-Positive T-Lymphocytes ; metabolism ; CX3C Chemokine Receptor 1 ; Cytokines ; blood ; Diabetes Mellitus, Experimental ; genetics ; therapy ; Enzyme-Linked Immunosorbent Assay ; Histone Code ; Histone Deacetylases ; genetics ; Mice ; Mice, Inbred NOD ; RNA, Messenger ; metabolism ; RNA, Small Interfering ; genetics ; therapeutic use ; Random Allocation ; Real-Time Polymerase Chain Reaction ; Receptors, CCR5 ; metabolism ; Receptors, Chemokine ; metabolism ; Spleen ; cytology

In light of the anti-inflammatory properties of histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), we examined a new HDAC inhibitor KBH-A42 for its anti-inflammatory activities. KBH-A42 showed noteworthy anti-inflammatory properties in vitro via suppression of the production of TNF-alpha, a proinflammatory cytokine, and nitric oxide (NO), a proinflammatory effector molecule, in LPS-stimulated RAW264.7 cells and peritoneal macrophages. It also inhibited TNF-alpha production in vivo as demonstrated in a LPS-induced mouse endotoxemia model. The levels of TNF-alpha, IL-1beta, IL-6 and iNOS mRNAs determined by RT-PCR propose that the inhibition of these pro-inflammatory mediators by KBH-A42 resulted from inhibiting expression of these genes. However, the EMSA study to see the effect of KBH-A42 on the binding of NF-kappaB, a transcription factor, to a specific DNA sequence showed that the binding of NF-kappaB to DNA was not changed regardless of increasing the concentration of KBH-A42 in the presence and absence of LPS stimulation. Interestingly, DNA binding of another transcription factor AP-1 dose-dependently increased by KBH-A42. KBH-A42 differentially regulated the phosphorylation of MAP kinases. While the phosphprylation of ERK1/2 and SAPK/JNK was not affected by KBH-A42, the phosphorylation of p38 decreased by KBH-A42. These results showed that KBH-A42 inhibits production of proinflammatory cytokines in macrophages by decreasing their mRNA levels, and p38 kinase is involved in the KBH-A42-mediated inhibition.
Animals ; Blotting, Western ; Cell Line ; Cell Survival/drug effects ; Cytokines/blood/genetics/*metabolism ; Electrophoretic Mobility Shift Assay ; Endotoxemia/blood/metabolism/pathology ; Enzyme Inhibitors/chemistry/*pharmacology ; Histone Deacetylases/*antagonists & inhibitors ; Hydroxamic Acids/chemistry/*pharmacology ; Interleukin-1beta/genetics/metabolism ; Interleukin-6/genetics/metabolism ; Macrophages/cytology/*drug effects/metabolism ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Molecular Structure ; NF-kappa B/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/genetics/metabolism ; Phosphorylation/drug effects ; Piperidones/chemistry/*pharmacology ; Protein Binding/drug effects ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factor AP-1/metabolism ; Tumor Necrosis Factor-alpha/blood/genetics/metabolism