Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone morphogenetic protein receptor 2 (BMPR2) mutations have been linked to familial pulmonary arterial hypertension (PAH), but the molecular pathways leading to this severe pathology remain poorly characterized. We report that hypoxia, a paramount stimulus for the development of pulmonary hypertension, suppresses the expression of inhibitor of differentiation 1 (Id1), a downstream target of the BMPR2 pathway, in human pulmonary artery smooth muscle cells (HPASMC). This attenuation of BMP signaling by hypoxia is conveyed through a repression of the transcriptional activity of the BMP responsive element (BRE) through mechanisms involving the transcriptional corepressor C-terminal-binding protein 1 (CtBP-1) and histone deacetylases (HDACs). Concordantly, overexpression of CtBP-1 suppressed BMP signaling, whereas small interfering RNA against CtBP-1 efficiently enhanced BMP stimulation of Id1 gene expression. Scavengers of reactive oxygen species had no effect on the hypoxic regulation of Id1, but, significantly, enhancement of the intracellular NADH/NAD(+) ratio mimicked the effects of hypoxia. These results indicate that attenuation of BMP signaling can occur through modulation of CtBP-1 activity by hypoxia-induced changes in the NADH/NAD(+) ratio. Our findings, taken in context with the observed prevalence of pulmonary arterial hypertension associated with BMPR2 mutations, define converging molecular pathways that lead to the development of pulmonary hypertension, through either genetic or epigenetic loss of function of components of the BMP signaling pathway.
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PMID:Hypoxia regulates bone morphogenetic protein signaling through C-terminal-binding protein 1. 1684 Jul 20

Thirty silent lupus nephritis (SLN) patients were compared to 16 individuals bearing overt lupus nephritis (OLN). Results included: years of systemic lupus erythematosus (SLE) diagnosis were significantly earlier (4.6 +/- 2.8 years) in SLN than in OLN (7.18 +/- 3.61) (P < 0.05). Neurological compromise, hypertension, normocitic anemia and lymphopenia were significantly prevalent in OLN than in SLN (P < 0.05). Beside normal urinary sediment and renal function tests, the SLN group showed a moderate increase of both activity (AI) and chronicity (CI) renal pathology index when compared to highly increased AI and CI in OLN (P < 0.05). Seventy percent of SLN patients were ISN/RPS Classes I (6.6%) and II (63.3%) while 81% of OLN cases were Classes III, IV (37.5%) and V. IgG, IgA, IgM, lambda chain, C3 and fibrinogen immune deposits were found in 90% or over in both SLN and OLN individuals while in 60% or over, both groups also showed kappa chain, Clq and C4 deposits. While prevalence of ANA, anti-dsDNA and anti-C1q antibodies were similar in both groups, anti-histone, anti-RNP, CIC and CH50 serum levels were significantly different in OLN versus SLN (P < 0.05). We strongly suggest that indeed SLN is the earliest stage in the natural history of lupus nephritis.
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PMID:Further description of early clinically silent lupus nephritis. 1721 89

In response to pathologic stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is characterized by myocyte hypertrophy, myocyte death and fibrosis, resulting in impaired cardiac function and heart failure. Cardiac remodeling is associated with derepression of genes that contribute to disease progression. This review focuses on evidence linking members of the Ca(2+)/calmodulin-dependent protein kinase (CaMK) superfamily, specifically CaMKII, protein kinase D (PKD) and microtubule associated kinase (MARK), to stress-induced derepression of pathological cardiac gene expression through their effects on class IIa histone deacetylases (HDACs).
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PMID:Derepression of pathological cardiac genes by members of the CaM kinase superfamily. 1721 38

Naturally occurring repeat sequences capable of adopting H-DNA structures are abundant in promoters of disease-related genes. In support of this, we found (CT)(22) . (AG)(22) repeats in the promoter of smooth muscle myosin light chain kinase (smMLCK), a key regulator of vascular smooth muscle function. We also found an insertion mutation that adds another six pairs of CT . AG repeats and increases smMLCK promoter activity in spontaneously hypertensive rats (SHR). Therefore, we used the smMLCK promoters from normotensive and hypertensive rats as a model system to determine how CT . AG repeats form H-DNA, an intramolecular triplex, and regulate promoter activity. High-resolution mapping with a chemical probe selective for H-DNA showed that the CT . AG repeats adopt H-DNA structures at a neutral pH. Importantly, the SHR promoter forms longer H-DNA structures than the promoter from normotensive rats. Reconstituting nucleosomes on the promoters, in vitro, showed no difference in nucleosome positioning between the two promoters. However, chromatin immunoprecipitation analyses revealed that histone acetylations are greater in the hypertensive promoter. Thus, our findings suggest that the extended CT . AG repeats in the SHR promoter increase H-DNA structures, histone modifications, and promoter activity of the smMLCK, perhaps contributing to vascular disorders in hypertension.
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PMID:Naturally extended CT . AG repeats increase H-DNA structures and promoter activity in the smooth muscle myosin light chain kinase gene. 1799 97

The advent of the epigenetic era has sparked a new frontier in molecular research and the understanding of how development can be regulated beyond direct alterations of the genome. Thus far, the focal point of epigenetic regulation during development has been chromatin modifications that control differential gene expression by DNA methylation and histone alterations. But what of events that alter gene expression without direct influence on the DNA itself? The present review focuses on epigenetic pathways regulating development from oogenesis to organogenesis and back that do not involve methylation of cytosine in DNA. We discuss target components of epigenetic modification such as organelle development, compartmentalisation of maternal factors and molecular mediators in the oocyte and how these factors acting during oogenesis impact on later development. Epigenetic regulation of development, be it via cytosine methylation or not, has wide-ranging effects on the subsequent success of a pregnancy and the intrinsic health of offspring. Perturbations in epigenetic regulation have been clearly associated with disease states in adult offspring, including Type II diabetes, hypertension, cancers and infertility. A clear understanding of all epigenetic mechanisms is paramount when considering the increased use of assisted reproductive techniques and the risks associated with their use.
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PMID:Epigenetic regulation during mammalian oogenesis. 1815 1

Curcumin, a commonly available spice and alternative medicine, has been tested in the laboratory and the clinic for activity against a wide range of diseases. It is thought to possess antiinflammatory and antioxidant activities and may also function to inhibit histone acetyl transferases, which activate gene expression via chromatin remodeling. Two reports in this issue of the JCI, by Morimoto et al. and Li et al., suggest that curcumin may inhibit cardiac hypertrophy in rodent models and provide beneficial effects after myocardial infarction or in the setting of hypertension (see the related articles beginning on pages 868 and 879, respectively). These results will spur further mechanistic inquiry into the role of chromatin remodeling in the regulation of cardiac homeostasis.
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PMID:Currying favor for the heart. 1829 9

Neonatal brain iron deficiency occurs after insufficient maternal dietary iron intake, maternal hypertension, and maternal diabetes mellitus and results in short and long-term neurologic and behavioral deficits. Early iron deficiency affects the genomic profile of the developing hippocampus that persists despite iron repletion. The purpose of the present study was threefold: 1) quantitative PCR confirmation of our previous microarray results, demonstrating upregulation of a network of genes leading to beta-amyloid production and implicated in Alzheimer disease etiology in iron-deficient anemic rat pups at the time of hippocampal differentiation; 2) investigation of the potential contributions of iron deficiency anemia and iron treatment to this differential gene expression in the hippocampus; and 3) investigation of these genes over a developmental time course in a mouse model where iron deficiency is limited to hippocampus, is not accompanied by anemia and is not repletable. Quantitative PCR confirmed altered regulation in 6 of 7 Alzheimer-related genes (Apbb1, C1qa, Clu, App, Cst3, Fn1, Htatip) in iron-deficient rats relative to iron-sufficient controls at P15. Comparison of untreated to treated iron-deficient animals at this age suggested the strong role of iron deficiency, not treatment, in the upregulation of this gene network. The non-anemic hippocampal iron-deficient mouse demonstrated upregulation of all 7 genes in this pathway from P5 to P25. Our results suggest a role for neonatal iron deficiency in dysregulation of genes that may set the stage for long-term neurodegenerative disease and that this may occur through a histone modification mechanism.
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PMID:Iron deficiency alters expression of genes implicated in Alzheimer disease pathogenesis. 1872 4

In eukaryotic nuclei, genomic DNA is compacted with histone and nonhistone proteins into a dynamic polymer termed chromatin. Reorganization of chromatin structure through histone modifications, the action of chromatin factors, or DNA methylation, can profoundly change gene expression. These epigenetic modifications allow heritable and potentially reversible changes in gene functioning to occur without altering the DNA sequence, thus extending the information potential of the genetic code. This review provides an introduction to epigenetic concepts for renal investigators and an overview of our work detailing an epigenetic pathway for aldosterone signaling and the control of epithelial Na(+) channel-alpha (ENaCalpha) subunit gene expression in the collecting duct. This new pathway involves a nuclear repressor complex, consisting of histone H3 Lys-79 methyltransferase disruptor of telomeric silencing-1a (Dot1a), ALL1 fused gene from chromosome 9 (Af9), a sequence-specific DNA-binding protein that binds the ENaCalpha promoter, and potentially other nuclear proteins. This complex regulates targeted histone H3 Lys-79 methylation of chromatin associated with the ENaCalpha promoter, thereby suppressing its transcriptional activity. Aldosterone disrupts the Dot1a-Af9 interaction by serum- and glucocorticoid-induced kinase-1 phosphorylation of Af9, and inhibits Dot1a and Af9 expression, resulting in histone H3 Lys-79 hypomethylation at specific subregions, and derepression of the ENaCalpha promoter. The Dot1a-Af9 pathway may also be involved in the control of genes implicated in renal fibrosis and hypertension.
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PMID:Epigenetics and the control of epithelial sodium channel expression in collecting duct. 1881 87

It has recently been increasingly recognised that disturbed intra-uterine development may impact on renal and cardiovascular risk in adult life, e.g. albuminuria and chronic kidney disease, hypertension, type 2 diabetes or cardiovascular events. According to Barker's hypothesis, when resources in utero are restricted, their allocation to the development of the kidney and pancreatic islets is restricted to guarantee appropriate development of the brain and heart. The underlying epigenetic mechanisms involve modification of gene expression by altered DNA methylation and histone acetylation as well as by allocation of stem cells. The result of this trade-off between the brain and kidney during organogenesis is a diminished number of nephrons ('nephron underdosing') which predisposes to albuminuria and risk of chronic kidney disease, as well as hypertension. In parallel, changed appetite centres, insulin resistance and beta-cell development predispose to obesity, metabolic syndrome and type 2 diabetes and the resulting renal sequelae. Numerous factors may trigger intra-uterine restriction of fetal growth, such as uterine underperfusion, maternal malnutrition, hyperglycaemia and hyperinsulinaemia of the mother, smoking or medications.
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PMID:Prenatal causes of kidney disease. 1916 17

Protein arginine methylation is a novel posttranslational modification regulating a diversity of cellular processes, including protein-protein interaction, signal transduction, or histone function. It has recently been shown to be dysregulated in chronic renal, vascular, and pulmonary diseases, and metabolic products originating from protein arginine methylation have been suggested to serve as biomarkers in cardiovascular and pulmonary diseases. Protein arginine methylation is performed by a class of enzymes called protein arginine methyltransferases (PRMT), which specifically methylate protein-incorporated arginine residues to generate protein-incorporated monomethylarginine (MMA), symmetric dimethylarginine (SDMA), or asymmetric dimethylarginine (ADMA). Upon proteolytic cleavage of arginine-methylated proteins, free intracellular MMA, SDMA, or ADMA is generated, which, upon secretion into the extracellular space (including plasma), directly affects the methylarginine concentration in the plasma. Free methylarginines are cleared from the body by renal excretion or hepatic metabolism. In addition, MMA and ADMA, but not SDMA, can be degraded via a class of intracellular enzymes called dimethylarginine dimethylaminohydrolases (DDAH). ADMA and MMA are endogenous inhibitors of nitric oxide synthases (NOS) and ADMA has been suggested to serve as a biomarker of endothelial dysfunction in cardiovascular diseases. This view has now been extended to the idea that, in addition to serum ADMA, the amount of free, as well as protein-incorporated, intracellular ADMA influences pulmonary cell function and determines the development of chronic lung diseases, including pulmonary arterial hypertension (PAH) or pulmonary fibrosis. This review will present and discuss the recent findings of dysregulated arginine methylation in chronic lung disease. We will highlight novel directions for future investigations evaluating the functional contribution of arginine methylation in lung homeostasis and disease with the outlook that modifying PRMT or DDAH activity presents a novel therapeutic option for the treatment of chronic lung disease.
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PMID:From arginine methylation to ADMA: a novel mechanism with therapeutic potential in chronic lung diseases. 1917 98


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