56 research outputs found
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Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series)
Abstract Epigenetics refers to heritable traits that are not a consequence of DNA sequence. Three classes of epigenetic regulation exist: DNA methylation, histone modification, and noncoding RNA action. In the cardiovascular system, epigenetic regulation affects development, differentiation, and disease propensity or expression. Defining the determinants of epigenetic regulation offers opportunities for novel strategies for disease prevention and treatment
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Bone Morphogenetic Proteinâ2 Decreases MicroRNAâ30b and MicroRNAâ30c to Promote Vascular Smooth Muscle Cell Calcification
Background: Vascular calcification resembles bone formation and involves vascular smooth muscle cell (SMC) transition to an osteoblastâlike phenotype to express Runx2, a master osteoblast transcription factor. One possible mechanism by which Runx2 protein expression is induced is downregulation of inhibitory microRNAs (miR). Methods and Results: Human coronary artery SMCs (CASMCs) treated with bone morphogenetic proteinâ2 (BMPâ2; 100 ng/mL) demonstrated a 1.7âfold (P<0.02) increase in Runx2 protein expression at 24 hours. A miR microarray and target prediction database analysis independently identified miRâ30b and miRâ30c (miRâ30bâc) as miRs that regulate Runx2 expression. Realâtimeâpolymerase chain reaction confirmed that BMPâ2 decreased miRâ30b and miRâ30c expression. A luciferase reporter assay verified that both miRâ30b and miRâ30c bind to the 3âČâuntranslated region of Runx2 mRNA to regulate its expression. CASMCs transfected with antagomirs to downregulate miRâ30bâc demonstrated significantly increased Runx2, intracellular calcium deposition, and mineralization. Conversely, forced expression of miRâ30bâc by transfection with preâmiRâ30bâc prevented the increase in Runx2 expression and mineralization of SMCs. Calcified human coronary arteries demonstrated higher levels of BMPâ2 and lower levels of miRâ30b than did noncalcified donor coronary arteries. Conclusions: BMPâ2 downregulates miRâ30b and miRâ30c to increase Runx2 expression in CASMCs and promote mineralization. Strategies that modulate expression of miRâ30b and miRâ30c may influence vascular calcification
Selenoprotein gene nomenclature
The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates
Selenium, a Micronutrient That Modulates Cardiovascular Health via Redox Enzymology
Selenium (Se) is a trace nutrient that promotes human health through its incorporation into selenoproteins in the form of the redox-active amino acid selenocysteine (Sec). There are 25 selenoproteins in humans, and many of them play essential roles in the protection against oxidative stress. Selenoproteins, such as glutathione peroxidase and thioredoxin reductase, play an important role in the reduction of hydrogen and lipid hydroperoxides, and regulate the redox status of Cys in proteins. Emerging evidence suggests a role for endoplasmic reticulum selenoproteins, such as selenoproteins K, S, and T, in mediating redox homeostasis, protein modifications, and endoplasmic reticulum stress. Selenoprotein P, which functions as a carrier of Se to tissues, also participates in regulating cellular reactive oxygen species. Cellular reactive oxygen species are essential for regulating cell growth and proliferation, protein folding, and normal mitochondrial function, but their excess causes cell damage and mitochondrial dysfunction, and promotes inflammatory responses. Experimental evidence indicates a role for individual selenoproteins in cardiovascular diseases, primarily by modulating the damaging effects of reactive oxygen species. This review examines the roles that selenoproteins play in regulating vascular and cardiac function in health and disease, highlighting their antioxidant and redox actions in these processes
The Link Between Hyperhomocysteinemia and Hypomethylation
Increased levels of homocysteine have been established as a risk factor for cardiovascular disease (CVD) by mechanisms still incompletely defined. S-Adenosylhomocysteine (SAH) is the metabolic precursor of homocysteine that accumulates in the setting of hyperhomocysteinemia and is a negative regulator of most cell methyltransferases. Several observations, summarized in the current review, support the concept that SAH, rather than homocysteine, may be the culprit in the CVD risk that has been associated with hyperhomocysteinemia. This review examines the biosynthesis and catabolism of homocysteine and how these pathways regulate accumulation of SAH. In addition, the epidemiological and experimental links between hyperhomocysteinemia and CVD are discussed, along with the evidence suggesting a role for SAH in the disease. Finally, the effects of SAH on the hypomethylation of DNA, RNA, and protein are examined, with an emphasis on how specific molecular targets may be mediators of homocysteine-associated vascular disease
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Systems Pharmacology and Rational Polypharmacy: Nitric OxideâCyclic GMP Signaling Pathway as an Illustrative Example and Derivation of the General Case
Impaired nitric oxide (NOË)-cyclic guanosine 3', 5'-monophosphate (cGMP) signaling has been observed in many cardiovascular disorders, including heart failure and pulmonary arterial hypertension. There are several enzymatic determinants of cGMP levels in this pathway, including soluble guanylyl cyclase (sGC) itself, the NOË-activated form of sGC, and phosphodiesterase(s) (PDE). Therapies for some of these disorders with PDE inhibitors have been successful at increasing cGMP levels in both cardiac and vascular tissues. However, at the systems level, it is not clear whether perturbation of PDE alone, under oxidative stress, is the best approach for increasing cGMP levels as compared with perturbation of other potential pathway targets, either alone or in combination. Here, we develop a model-based approach to perturbing this pathway, focusing on single reactions, pairs of reactions, or trios of reactions as targets, then monitoring the theoretical effects of these interventions on cGMP levels. Single perturbations of all reaction steps within this pathway demonstrated that three reaction steps, including the oxidation of sGC, NOË dissociation from sGC, and cGMP degradation by PDE, exerted a dominant influence on cGMP accumulation relative to other reaction steps. Furthermore, among all possible single, paired, and triple perturbations of this pathway, the combined perturbations of these three reaction steps had the greatest impact on cGMP accumulation. These computational findings were confirmed in cell-based experiments. We conclude that a combined perturbation of the oxidatively-impaired NOË-cGMP signaling pathway is a better approach to the restoration of cGMP levels as compared with corresponding individual perturbations. This approach may also yield improved therapeutic responses in other complex pharmacologically amenable pathways
Relative cGMP<sub>T</sub> levels after single, paired, and triple kinetic perturbations of the oxidatively impaired NOË-cGMP pathway.
<p>The relative level of cGMP<sub>T</sub> as a function of all possible single (13 brown bars), paired (78 gray bars), and triple (286 green bars) perturbations is shown. Values of the rate constants were reduced to 10% of their original values (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004822#pcbi.1004822.s002" target="_blank">S1 Table</a>). Each bar shows the relative integrated cGMP levels over the period of simulation, or . Note that some of the optimal perturbations are highlighted in this figure.</p
The effects of linear reduction of values for three individual rate constants on cGMP dynamics.
<p>Using the linear reduction of values for k<sub>1</sub>, k<sub>3</sub>, and k<sub>10</sub>, we created a vector of eleven different values for each of these rate constants. We next generated three linearly spaced vectors for each of the rate constants by fractionally reducing each decrementally. Using these vectors of rate constants, cGMP dynamics were calculated. The cGMP levels after serial reduction of (A) k<sub>1</sub>, (B) k<sub>2</sub>, and (C) k<sub>3</sub>. (D) The relative cGMP levels. Data are shown as mean (dashed lines) ± S.E.M (shaded lines) of 11 simulated replicates. Note: k<sub>3</sub> was the most sensitive parameter in cGMP accumulation as compared with k<sub>1</sub> and k<sub>10</sub>. In addition, the highest cGMP levels were achieved at ~40 seconds.</p
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