Inhibition of HDAC3 and ATXN3 by miR-25 prevents neuronal loss and ameliorates neurological recovery in cerebral stroke experimental rats

Journal of Physiology and Biochemistry - HDAC3 plays important role in regulating memory and plasticity of neurons. We studied the role of miR-25 against HDAC3-induced neuronal injury in acute...     

组蛋白去乙酰基转移酶2在疾病中的研究进展

HDAC2是Ⅰ类组蛋白去乙酰基转移酶,能够促进激素和依赖细胞因子的信号转导.HDAC2是口腔癌、前列腺癌、卵巢癌、子宫内膜癌以及胃癌特异的肿瘤标记物;对肌肉和心脏相关疾病,胚胎发育、神经功能都有重要影响.药物研发和药物介入技术选择HDAC2为精确的靶标已经证明是一个有效的治疗方法.本文对HDAC2在正常和相关疾病中的作用进行了总结.     

Histone deacetylase 10, a potential epigenetic target for therapy

Histone deacetylase (HDAC) 10, a class II family, has been implicated in various tumors and non-tumor diseases, which makes the discovery of biological functions and novel inhibitors a fundamental endeavor. In cancers, HDAC10 plays crucial roles in regulating various cellular processes through its epigenetic functions or targeting some decisive molecular or signaling pathways. It also has potential clinical utility for targeting tumors and non-tumor diseases, such as renal cell carcinoma, prostate cancer, immunoglobulin A nephropathy (IgAN), intracerebral hemorrhage, human immunodeficiency virus (HIV) infection and schizophrenia. To date, relatively few studies have investigated HDAC10-specific inhibitors. Therefore, it is important to study the biological functions of HDAC10 for the future development of specific HDAC10 inhibitors. In this review, we analyzed the biological functions, mechanisms and inhibitors of HDAC10, which makes HDAC10 an appealing therapeutic target.     

The role of SIRT2 in vascular-related and heart-related diseases: A review

At present, cardiovascular disease is one of the important factors of human death, and there are many kinds of proteins involved. Sirtuins family proteins are involved in various physiological and pathological activities of the human body. Among them, there are more and more studies on the relationship between sirtuin2 (SIRT2) protein and cardiovascular diseases. SIRT2 can effectively inhibit pathological cardiac hypertrophy. The effect of SIRT2 on ischaemia-reperfusion injury has different effects under different conditions. SIRT2 can reduce the level of reactive oxygen species (ROS), which may help to reduce the severity of diabetic cardiomyopathy. SIRT2 can affect a variety of cardiovascular diseases, energy metabolism and the ageing of cardiomyocytes, thereby affecting heart failure. SIRT2 also plays an important role in vascular disease. For endothelial cell damage used by oxidative stress, the role of SIRT2 is bidirectional, which is related to the degree of oxidative stress stimulation. When the degree of stimulation is small, SIRT2 plays a protective role, and when the degree of stimulation increases to a certain level, SIRT2 plays a negative role. In addition, SIRT2 is also involved in the remodelling of blood vessels and the repair of skin damage.     

Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity

Co-repressor histone deacetylase 9 (HDAC9) plays a key role in the development and differentiation of many types of cells, including regulatory T cells. However, the biological function of HDAC9 in T effector cells is unknown. Systemic autoimmune diseases like lupus, diabetes, and rheumatoid arthritis have dysfunctional effector T cells. To determine the role of HDAC9 in systemic autoimmunity, we created MRL/lpr mice with HDAC9 deficiency that have aberrant effector T cell function. HDAC9 deficiency led to decreased lympho-proliferation, inflammation, autoantibody production, and increased survival in MRL/lpr mice. HDAC9-deficient mice manifested Th2 polarization, decreased T effector follicular cells positive for inducible co-stimulator, and activated T cells in vivo compared with HDAC9-intact MRL/lpr mice. HDAC9 deficiency also resulted in increased GATA3 and roquin and decreased BCL6 gene expression. HDAC9 deficiency was associated with increased site-specific lysine histone acetylation at H3 (H3K9, H3K14, and H3K18) globally that was localized to IL-4, roquin, and peroxisome proliferator-activated receptor-γ promoters with increased gene expression, respectively. In kidney and spleen, HDAC9 deficiency decreased inflammation and cytokine and chemokine production due to peroxisome proliferator-activated receptor γ overexpression. These findings suggest that HDAC9 acts as an epigenetic switch in effector T cell-mediated systemic autoimmunity.     

aPKC Phosphorylation of HDAC6 Results in Increased Deacetylation Activity

The Class II histone deacetylase, HDAC6, has been shown to be involved in cell motility, aggresome formation and mitochondria transport. HDAC6 deacetylase activity regulates α-tubulin acetylation levels and thus plays a critical role in these processes. In turn, HDAC6 activity can be regulated by interaction with various proteins including multiple kinases. Kinase mediated phosphorylation of HDAC6 can lead to either increased or reduced activity. Our previous research has shown that sequestosome1/p62 (SQSTM1/p62) interacts with HDAC6 and regulates its activity. As SQSTM1/p62 is a scaffolding protein known to interact directly with the zeta isoform of Protein Kinase C (PKCζ), we sought to examine if HDAC6 could be a substrate for PKCζ phosphorylation and if so, how its activity might be regulated. Our data demonstrate that HDAC6 is not only present in a protein complex with PKCζ but can also be phosphorylated by PKCζ. We also show that specific phosphorylation of HDAC6 by PKCζ increases HDAC6 deacetylase activity resulting in reduced acetylated tubulin levels. Our findings provide novel insight into the molecular mechanism by which HDAC6, PKCζ and SQSTM1/p62 function together in protein aggregate clearance. These results also highlight a new research direction which may prove fruitful for understanding the underlying cause of several neurodegenerative diseases.     

MicroRNAs在心血管自噬中的调节作用

自噬作为一种进化上高度保守的细胞降解途径,其调节异常与心血管疾病的发生、发展密切相关.研究显示,在心血管系统中,基础水平自噬对维持心肌正常收缩和传导至关重要,而在缺血/再灌注损伤和心力衰竭等心血管病理状态下,自噬水平明显增强.细胞自噬是一种多基因参与的复杂过程,近年来越来越多的证据表明,microRNAs(miRNAs)在心血管系统发育、正常生理功能维持以及不同心血管疾病(cardiovascular disease,CVDs)自噬中具有重要调节作用.本文通过对miRNAs与CVDs自噬调节方面的进展进行归纳,针对miRNAs对CVDs自噬的潜在机制进行总结,望为心血管疾病的诊断和治疗提供新的方向.     

Thioredoxin-interacting protein mediates NALP3 inflammasome activation in podocytes during diabetic nephropathy

Numerous studies have shown that the NALP3 inflammasome plays an important role in various immune and inflammatory diseases. However, whether the NALP3 inflammasome is involved in the pathogenesis of diabetic nephropathy (DN) is unclear. In our study, we confirmed that high glucose (HG) concentrations induced NALP3 inflammasome activation both in vivo and in vitro. Blocking NALP3 inflammasome activation by NALP3/ASC shRNA and caspase-1 inhibition prevented IL-1β production and eventually attenuated podocyte and glomerular injury under HG conditions. We also found that thioredoxin (TRX)-interacting protein (TXNIP), which is a pro-oxidative stress and pro-inflammatory factor, activated NALP3 inflammasome by interacting with NALP3 in HG-exposed podocytes. Knocking down TXNIP impeded NALP3 inflammasome activation and alleviated podocyte injury caused by HG. In summary, the NALP3 inflammasome mediates podocyte and glomerular injury in DN, moreover, TXNIP participates in the formation and activation of the NALP3 inflammasome in podocytes during DN, which represents a novel mechanism of podocyte and glomerular injury under diabetic conditions.     

Deacetylase-dependent and -independent role of HDAC3 in cardiomyopathy

Cardiomyopathy is a common disease of cardiac muscle that negatively affects cardiac function. HDAC3 commonly functions as corepressor by removing acetyl moieties from histone tails. However, a deacetylase-independent role of HDAC3 has also been described. Cardiac deletion of HDAC3 causes reduced cardiac contractility accompanied by lipid accumulation, but the molecular function of HDAC3 in cardiomyopathy remains unknown. We have used powerful genetic tools in Drosophila to investigate the enzymatic and nonenzymatic roles of HDAC3 in cardiomyopathy. Using the Drosophila heart model, we showed that cardiac-specific HDAC3 knockdown (KD) leads to prolonged systoles and reduced cardiac contractility. Immunohistochemistry revealed structural abnormalities characterized by myofiber disruption in HDAC3 KD hearts. Cardiac-specific HDAC3 KD showed increased levels of whole-body triglycerides and increased fibrosis. The introduction of deacetylase-dead HDAC3 mutant in HDAC3 KD background showed comparable results with wild-type HDAC3 in aspects of contractility and Pericardin deposition. However, deacetylase-dead HDAC3 mutants failed to improve triglyceride accumulation. Our data indicate that HDAC3 plays a deacetylase-independent role in maintaining cardiac contractility and preventing Pericardin deposition as well as a deacetylase-dependent role to maintain triglyceride homeostasis.     

Histone deacetylase 2 regulates ULK1 mediated pyroptosis during acute liver failure by the K68 acetylation site

Pyroptosis is a new necrosis pattern of hepatocyte during liver inflammation in acute liver failure (ALF). Histone deacetylase 2 (HDAC2) is associated with several pathological conditions in the liver system. The aim of this study is to investigate whether knockdown or pharmacological inhibition of HDAC2 could reduce the level of pyroptosis in ALF through ULK1-NLRP3-pyroptosis pathway. The role of HDAC2 on ULK1-NLRP3-pyroptosis pathway during ALF was detected in clinical samples. The mechanism was investigated in transfected cells or in ALF mouse model. The RNA-sequencing results revealed that ULK1 was a negative target regulatory molecule by HDAC2. During the process of pyroptosis, the HDAC2 exerted the antagonistic effect with ULK1 by the K68 acetylation site in L02 cells. Then the role of HDAC2 on ULK1-NLRP3-pyroptosis pathway in ALF mouse model was also detected. Moreover, the related molecules to ULK1-NLRP3-pyroptosis pathway were verified different expression in normal health donors and clinical ALF patients. HDAC2 in hepatocytes plays a pivotal role in an ULK1-NLRP3 pathway driven auto-amplification of pyroptosis in ALF. One of the important mechanisms is that inhibition HDAC2 to reduce pyroptosis may be by modulating the K68 lysine site of ULK1.Subject terms: Acetylation, Hepatotoxicity     

Recent advances in class IIa histone deacetylases research

Epigenetic control plays an important role in gene regulation through chemical modifications of DNA and post-translational modifications of histones. An essential post-translational modification is the histone acetylation/deacetylation-process which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The mammalian zinc dependent HDAC family is subdivided into three classes: class I (HDACs 1-3, 8), class II (IIa: HDACs 4, 5, 7, 9; IIb: HDACs 6, 10) and class IV (HDAC 11). In this review, recent studies on the biological role and regulation of class IIa HDACs as well as their contribution in neurodegenerative diseases, immune disorders and cancer will be presented. Furthermore, the development, synthesis, and future perspectives of selective class IIa inhibitors will be highlighted.     

HDAC9 exacerbates endothelial injury in cerebral ischaemia/reperfusion injury

Histone deacetylase (HDAC) 9, a member of class II HDACs, regulates a wide variety of normal and abnormal physiological functions, which is usually expressed at high levels in the brain and skeletal muscle. Although studies have highlighted the importance of HDAC‐mediated epigenetic processes in the development of ischaemic stroke and very recent genome‐wide association studies have identified a variant in HDAC9 associated with large‐vessel ischemic stroke, the molecular events by which HDAC9 induces cerebral injury keep unclear. In this study, we found that HDAC9 was up‐regulated in the ischaemic cerebral hemisphere after cerebral ischaemia/reperfusion (I/R) injury in rats and in vivo gene silencing of HDAC9 by recombinated lentivirus infection in the brain reduced cerebral injury in experimental stroke. We further demonstrated that HDAC9 contributed to oxygen‐glucose deprivation‐induced brain microvessel endothelial cell dysfunction as demonstrated by the increased inflammatory responses, cellular apoptosis and endothelial cell permeability dysfunction accompanied by reduced expression of tight‐junction proteins. We further found that HDAC9 suppressed autophagy, which was associated with endothelial dysfunction. This study for the first time provides direct evidence that HDAC9 contributes to endothelial cell injury and demonstrates that HDAC9 is one of critical components of a signal transduction pathway that links cerebral injury to epigenetic modification in the brain.