Aims Tissue-type plasminogen activator (t-PA) is produced by endothelial cells (EC) and is responsible for the removal of intravascular fibrin deposits. We investigated whether expression of t-PA by EC is under epigenetic control. Methods and results Methylation analysis of the proximal t-PA promoter revealed a stretch of unmethylated CpG dinucleotides from pos- ition 2121 to +59, while upstream CpG dinucleotides were all methylated. In contrast, in human primary hepato- cytes, which express t-PA at much lower levels than EC, the proximal promoter was partially methylated. Treatment of EC with the non-specific histone deacetylase (HDAC) inhibitors butyrate and trichostatin and with MS275, a specific inhibitor of class I HDAC, resulted in a time- and dose-dependent increase in t-PA expression. Garcinol and anacardic acid, inhibitors of the histone acetyl transferases CBP/p300 and PCAF, reduced basal and HDAC inhibitor-induced t-PA expression, whereas curcumin, an inhibitor of CBP/p300 only, had no effect. We performed chromosome immunoprecipitation analysis of the t-PA promoter using antibodies specific for acetylated histone H3 or H4 and observed an increase in H3 acetylation of 10+3 and 44+14-fold in EC treated with trichostatin or MS275, respectively, and in H4 acetylation of 7.7+1.4 and 16+3-fold, respectively.
Epigenetic modifications, such as DNA methylation and histone acetylation, are crucial for homeostasis, and enable cells to respond quickly to environmental changes. However, epigenetic alterations are also associated with the development and progression of disease. The authors of this Review outline how epigenetics may contribute to cardiovascular disease, and highlight potential therapeutic agents that modify the epigenetic state, which could be used in the prevention or treatment of cardiovas...
Classical models of transcription in vascular endothelial cells, specifically the cis/trans paradigm, have limitations. For instance, how does the environment have chronic effects on gene expression in endothelial cells after weeks or years? When an endothelial cell divides, how is this information transmitted to daughter cells? Epigenetics refers to chromatin-based pathways important in the regulation of gene expression and includes three distinct, but highly interrelated, mechanisms: DNA methy...
Our genes code for the building blocks of our body, and variations in our genome predispose us to distinct traits, including disease. To add complexity to the interpretation and regulation of our genetic code, the DNA packed into the chromatin forming our chromosomes is modified by factors that alter its expressivity but without changing its sequence. These factors are referred to as epigenetic factors. A recent definition states: “An epigenetic trait is a stably heritable phenotype resulting fr...
Human cancer represents a heterogeneous group of diseases that are driven by progressive genetic and epigenetic abnormalities. The latter alterations involve hypermethylation and hypomethylation of DNA, and changed patterns of histone modification, with resultant remodeling of the chromatin structure that cause deregulation of the transcription activity of many genes. Unlike the remarkable progress in understanding the processes by which DNA methyltransferases can regulate gene expression and hi...
Inflammation involving the innate and adaptive immune systems is a normal response to infection. However, when allowed to continue unchecked, inflammation may result in autoimmune or autoinflammatory disorders, neurodegenerative disease, or cancer. A variety of safe and effective anti-inflammatory agents are available, including aspirin and other nonsteroidal anti-inflammatories, with many more drugs under development. In particular, the new era of anti-inflammatory agents includes "biologicals"...
Epigenetics is a rapidly growing field and holds great promise for a range of human diseases, including brain disorders such as Rett syndrome, anxiety and depressive disorders, schizophrenia, Alzheimer disease and Huntington disease. This review is concerned with the pharmacology of epigenetics to treat disorders of the epigenome whether induced developmentally or manifested/acquired later in life. In particular, we will focus on brain disorders and their treatment by drugs that modify the epige...
Last. Roberto Pili(Johns Hopkins University)H-Index: 69
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Solid tumor malignancies including breast, lung and prostate carcinomas are considered to be angiogenesis dependent. Tumor angiogenesis is often mediated by hypoxia secondary to tumor growth or by increased oncogenic signaling. Both mechanisms result in increased hypoxia-inducible factor-1 alpha (HIF-1α) signaling and its transcriptional target vascular endothelial growth factor (VEGF). Critical to HIF-1α signaling are post translational modifications including acetylation mediated by histone ac...
#1Paul A. Marks(MSK: Memorial Sloan Kettering Cancer Center)H-Index: 54
#2W.-S. Xu(MSK: Memorial Sloan Kettering Cancer Center)H-Index: 1
The role of histone deacetylases (HDAC) and the potential of these enzymes as therapeutic targets for cancer, neurodegenerative diseases and a number of other disorders is an area of rapidly expanding investigation. There are 18 HDACs in humans. These enzymes are not redundant in function. Eleven of the HDACs are zinc dependent, classified on the basis of homology to yeast HDACs: Class I includes HDACs 1, 2, 3, and 8; Class IIA includes HDACs 4, 5, 7, and 9; Class IIB, HDACs 6 and 10; and Class ...
#1Howard Cedar(HUJI: Hebrew University of Jerusalem)H-Index: 87
#2Yehudit Bergman(HUJI: Hebrew University of Jerusalem)H-Index: 40
Both DNA methylation and histone modification are involved in establishing patterns of gene repression during development. Certain forms of histone methylation cause local formation of heterochromatin, which is readily reversible, whereas DNA methylation leads to stable long-term repression. It has recently become apparent that DNA methylation and histone modification pathways can be dependent on one another, and that this crosstalk can be mediated by biochemical interactions between SET domain ...
#1W. Pan(UAB: University of Alabama at Birmingham)H-Index: 1
#2M. J. Chang(UAB: University of Alabama at Birmingham)H-Index: 1
Last. Edlue M. Tabengwa(UAB: University of Alabama at Birmingham)H-Index: 15
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Summary. Background: Wine polyphenol quercetin upregulates tissue-type plasminogen activator (t-PA) transcription in cultured human umbilical cord vein endothelial cells (HUVECs). However, the regulatory elements and signaling pathways involved in this regulation are unknown. Objectives: We aimed to localize quercetin-responsive t-PA promoter elements, identify the proteins that bind these elements, and decipher signaling pathways involved in the regulation of t-PA. Methods: To localize querceti...
Last. Qing R. Miao(NYU: New York University)H-Index: 1
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Endothelial cell (EC), consisting of the innermost cellular layer of all types of vessels, is not only a barrier composer but also performing multiple functions in physiological processes. It actively controls the vascular tone and the extravasation of water, solutes, and macromolecules; modulates circulating immune cells as well as platelet and leukocyte recruitment/adhesion and activation. In addition, EC also tightly keeps coagulation/fibrinolysis balance and plays a major role in angiogenesi...
Epigenetics, a term conventionally used to explain the intricate interplay between genes and the environment, is now regarded as the fundament of developmental biology. Several lines of evidence garnered over the past decades suggest that epigenetic alterations, mostly encompassing DNA methylation, histone tail modifications, and generation of microRNAs, play an important, though still incompletely explored, role in both primary and secondary hemostasis. Epigenetic variations may interplay with ...
Background Major Depressive Disorder (MDD) represents a tremendous health threat to the world’s population. Electroconvulsive therapy (ECT) is the most effective treatment option for refractory MDD patients. Ample evidence suggests brain-derived neurotrophic factor (BDNF) to play a crucial role in ECT´s mode of action. Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) are involved in BDNF production. Hypothesis The DNA methylation of gene regions encoding for...
#1Jiayi Zhu(HUST: Huazhong University of Science and Technology)H-Index: 1
#2Yan Wan(HUST: Huazhong University of Science and Technology)H-Index: 6
Last. Huijuan Jin(HUST: Huazhong University of Science and Technology)H-Index: 23
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Endogenous protease tissue-type plasminogen activator (tPA) has highly efficient fibrinolytic activity and its recombinant variants alteplase and tenecteplase are established as highly effective thrombolytic drugs for ischemic stroke. Endogenous tPA is constituted of five functional domains through which it interacts with a variety of substrates, binding proteins and receptors, thus having enzymatic and cytokine-like effects to act on all cell types of the brain. In the past 2 decades, numerous ...
: Autism spectrum disorders (ASDs) are neurodevelopmental disorders that share behavioral features, the results of numerous studies have suggested that the underlying causes of ASDs are multifactorial. Behavioral and/or neurobiological analyses of ASDs have been performed extensively using a valid model of prenatal exposure to valproic acid (VPA). Abnormal synapse formation resulting from altered neurite outgrowth in neural progenitor cells (NPCs) during embryonic brain development has been obse...
: Background Nasal polyps (NP) are characterized by pseudocysts derived from stromal tissue edema and cause persistent infections in patients with chronic rhinosinusitis (CRS). A low level of tissue-type plasminogen activator (gene name PLAT) is considered a cause of stromal tissue edema because of insufficient plasmin activation in NP; however, the mechanism regulating PLAT gene expression levels is still unclear. The epigenetic mechanism regulating the PLAT gene expression has been studied in ...
: This study aims to elucidate the prognostic and predictive biomarker of miR-495 and Stat3 in peripheral blood in relation to lower extremity deep venous thrombosis (DVT). Patients with lower limb fractures were assigned into case and control groups. Rats were allocated into blank (normal rats), sham (normal rats), DVT, miR-495 mimic, miR-495 inhibitor, over-Stat3, and si-Stat3 groups. ELISA was used to detect levels of prothrombin time (PT), endothelin-1 (ET-1), Human Fibrinogen (FIB), D-Dimer...
BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new str...
Last. Sverker Jern(University of Gothenburg)H-Index: 51
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Essentials Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. Valproic acid increased tissue plasminogen activator expression in vascular endothelium. Valproic acid reduced fibrin deposition and thrombus formation after vascular injury. SummaryBackground The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type pla...
#2Pia Larsson(University of Gothenburg)H-Index: 17
Last. Sverker Jern(University of Gothenburg)H-Index: 51
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Objective. Endothelial tissue-type plasminogen activator (t-PA) release is a pivotal response to protect the circulation from occluding thrombosis. We have shown that the t-PA gene is epigenetically regulated and greatly induced by the histone deacetylase (HDAC) inhibitor valproic acid (VPA). We now investigated involvement of known t-PA promoter regulatory elements and evaluated dependence of potential interacting transcription factors/cofactors. Methods. A reporter vector with an insert, separ...
