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)

NO acting through soluble guanylyl cyclase and cGMP formation is a negative regulator of cardiomyocyte hypertrophy. Downstream targets mediating the inhibitory effects of NO/cGMP on cardiomyocyte hypertrophy have not been elucidated. In addition to its antihypertrophic effects, NO promotes apoptosis in cardiomyocytes, presumably through cGMP-independent pathways. We investigated the role of cGMP-dependent protein kinase (PKG) in the antihypertrophic and proapoptotic effects of NO. Incubation of neonatal rat cardiomyocytes with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) (250 micromol/L) or the PKG-selective cGMP analog 8-pCPT-cGMP (500 micromol/L) activated endogenous PKG type I, as shown by the site-specific phosphorylation of vasodilator-stimulated phosphoprotein, a well-characterized PKG substrate. SNAP (250 micromol/L) and 8-pCPT-cGMP (500 micromol/L) modestly attenuated the hypertrophic response to alpha(1)-adrenergic stimulation with phenylephrine. Although a high concentration of SNAP (1000 micromol/L) promoted apoptosis in cardiomyocytes, as evidenced by the formation of histone-associated DNA fragments, antihypertrophic concentrations of SNAP (250 micromol/L) and 8-pCPT-cGMP (500 micromol/L) did not promote cell death. Because chronic activation downregulated endogenous PKG I, we explored whether gene transfer of PKG I would enhance the sensitivity of cardiomyocytes to the antihypertrophic effects of NO/cGMP. Indeed, after adenoviral overexpression of PKG Ibeta, SNAP (250 micromol/L) and 8-pCPT-cGMP (500 micromol/L) completely suppressed the hypertrophic response to alpha(1)-adrenergic stimulation. As observed in noninfected cells, SNAP (250 micromol/L) and 8-pCPT-cGMP (500 micromol/L) did not promote apoptosis in cardiomyocytes overexpressing PKG Ibeta. Moreover, overexpression of PKG Ibeta did not enhance the proapoptotic effects of 1000 micromol/L SNAP, implying PKG-independent effects of NO on apoptosis. Endogenous PKG I mediates antihypertrophic but not proapoptotic effects of NO in a cell culture model of cardiomyocyte hypertrophy. Adenoviral gene transfer of PKG I selectively enhances the antihypertrophic effects of NO without increasing the susceptibility to apoptosis.
Hypertension 2002 Jan
PMID:Gene transfer of cGMP-dependent protein kinase I enhances the antihypertrophic effects of nitric oxide in cardiomyocytes. 1179 84

Expression of replication-dependent histone genes requires a conserved hairpin RNA element in the 3' untranslated regions of poly(A)-less histone mRNAs. The 3' hairpin element is recognized by the hairpin-binding protein or stem-loop-binding protein (HBP/SLBP). This protein-RNA interaction is important for the endonucleolytic cleavage generating the mature mRNA 3' end. The 3' hairpin and presumably HBP/SLBP are also required for nucleocytoplasmic transport, translation, and stability of histone mRNAs. RNA 3' processing and mRNA stability are both regulated during the cell cycle. Here, we have determined the three-dimensional structure of a 24-mer RNA comprising a mammalian histone RNA hairpin using heteronuclear multidimensional NMR spectroscopy. The hairpin adopts a novel UUUC tetraloop conformation that is stabilized by base stacking involving the first and third loop uridines and a closing U-A base pair, and by hydrogen bonding between the first and third uridines in the tetraloop. The HBP interaction of hairpin RNA variants was analyzed in band shift experiments. Particularly important interactions for HBP recognition are mediated by the closing U-A base pair and the first and third loop uridines, whose Watson-Crick functional groups are exposed towards the major groove of the RNA hairpin. The results obtained provide novel structural insight into the interaction of the histone 3' hairpin with HBP, and thus the regulation of histone mRNA metabolism.
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PMID:Structure of the histone mRNA hairpin required for cell cycle regulation of histone gene expression. 1187 59

A 66-year-old man presented with widespread annular and bullous subacute cutaneous lupus erythematosus (SCLE), developed after starting treatment for hypertension with the calcium channel blocker nitrendipine. A few days after withdrawal of the drug, while cutaneous manifestations were improving, left hemiparesis occurred. Laboratory investigations showed, in addition to anti-Ro, anti-La and anti-histone antibodies, the presence of lupus anticoagulant, anticardiolipin antibodies, prolonged APTT and thrombocytopenia. On the basis of the spontaneous regression of the patient's skin lesions after discontinuation of the drug, a possible relationship between nitrendipine intake, the clinical events and the biological findings is discussed.
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PMID:Nitrendipine-induced subacute cutaneous lupus erythematosus. 1269 45

In 1996, a new method, termed the yeast three-hybrid system, dedicated to selection of RNA binding proteins using a hybrid RNA molecule as bait was described. In this minireview, we summarize the results that have been obtained using this method. Indeed, approximately 20 unknown proteins have been characterized so far. The three-hybrid strategy has also been used as a tool to dissect RNA-protein interactions. The example of such a study on human histone HBP interaction with its target mRNA is described. Problems that can be encountered are addressed in a troubleshooting section. Especially, our results with tRNA binding proteins are discussed.
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PMID:Results and prospects of the yeast three-hybrid system. 1470 17

The histone hairpin binding protein (HBP, also called SLBP, which stands for stem-loop binding protein) binds specifically to a highly conserved hairpin structure located in the 3' UTR of the cell-cycle-dependent histone mRNAs. HBP consists of a minimal central RNA binding domain (RBD) flanked by an N- and C-terminal domain. The yeast three-hybrid system has been used to investigate the critical residues of the human HBP involved in the binding of its target hairpin structure. By means of negative selections followed by positive selections, we isolated mutant HBP species. Our results indicate tight relationships between the RBD and the N- and C-terminal domains.
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PMID:Critical residues for RNA discrimination of the histone hairpin binding protein (HBP) investigated by the yeast three-hybrid system. 1470 61

Chronic ethanol abuse is associated with liver injury, neurotoxicity, hypertension, cardiomyopathy, modulation of immune responses and increased risk for cancer, whereas moderate alcohol consumption exerts protective effect on coronary heart disease. However, the signal transduction mechanisms underlying these processes are not well understood. Emerging evidences highlight a central role for mitogen activated protein kinase (MAPK) family in several of these effects of ethanol. MAPK signaling cascade plays an essential role in the initiation of cellular processes such as proliferation, differentiation, development, apoptosis, stress and inflammatory responses. Modulation of MAPK signaling pathway by ethanol is distinctive, depending on the cell type; acute or chronic; normal or transformed cell phenotype and on the type of agonist stimulating the MAPK. Acute exposure to ethanol results in modest activation of p42/44 MAPK in hepatocytes, astrocytes, and vascular smooth muscle cells. Acute ethanol exposure also results in potentiation or prolonged activation of p42/44MAPK in an agonist selective manner. Acute ethanol treatment also inhibits serum stimulated p42/44 MAPK activation and DNA synthesis in vascular smooth muscle cells. Chronic ethanol treatment causes decreased activation of p42/44 MAPK and inhibition of growth factor stimulated p42/44 MAPK activation and these effects of ethanol are correlated to suppression of DNA synthesis, impaired synaptic plasticity and neurotoxicity. In contrast, chronic ethanol treatment causes potentiation of endotoxin stimulated p42/44 MAPK and p38 MAPK signaling in Kupffer cells leading to increased synthesis of tumor necrosis factor. Acute exposure to ethanol activates pro-apoptotic JNK pathway and anti-apoptotic p42/44 MAPK pathway. Apoptosis caused by chronic ethanol treatment may be due to ethanol potentiation of TNF induced activation of p38 MAPK. Ethanol induced activation of MAPK signaling is also involved in collagen expression in stellate cells. Ethanol did not potentiate serum stimulated or Gi-protein dependent activation of p42/44 MAPK in normal hepatocytes but did so in embryonic liver cells and transformed hepatocytes leading to enhanced DNA synthesis. Ethanol has a 'triangular effect' on MAPK that involve direct effects of ethanol, its metabolically derived mediators and oxidative stress. Acetaldehyde, phosphatidylethanol, fatty acid ethyl ester and oxidative stress, mediate some of the effects seen after ethanol alone whereas ethanol modulation of agonist stimulated MAPK signaling appears to be mediated by phosphatidylethanol. Nuclear MAPKs are also affected by ethanol. Ethanol modulation of nuclear p42/44 MAPK occurs by both nuclear translocation of p42/44 MAPK and its activation in the nucleus. Of interest is the observation that ethanol caused selective acetylation of Lys 9 of histone 3 in the hepatocyte nucleus. It is plausible that ethanol modulation of cross talk between phosphorylation and acetylations of histone may regulate chromatin remodeling. Taken together, these recent developments place MAPK in a pivotal position in relation to cellular actions of ethanol. Furthermore, they offer promising insights into the specificity of ethanol effects and pharmacological modulation of MAPK signaling. Such molecular signaling approaches have the potential to provide mechanism-based therapy for the management of deleterious effects of ethanol or for exploiting its beneficial effects.
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PMID:MAP kinase signaling in diverse effects of ethanol. 1502 49

Diverse aetiological factors, including myocardial infarction, hypertension and contractile abnormalities, trigger a cardiac remodelling process in which the heart becomes abnormally enlarged with a consequent decline in cardiac function and eventual heart failure. Pathological cardiac hypertrophy is accompanied by the activation of a fetal cardiac gene programme, which contributes to maladaptive changes in contractility and calcium handling. Traditional treatment for heart failure involves administration of drugs that antagonize early signalling events at or near the cell membrane (e.g. cell surface receptor or ion channels). Given the complexity and redundant nature of the signalling networks that drive cardiac pathogenesis, a potentially more efficacious therapeutic strategy for disrupting the disease process would be to target common downstream elements in pathological signalling cascades. We have shown that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking class II HDACs are sensitized to hypertrophic signals. Paradoxically, HDAC inhibitors also block cardiac hypertrophy and fetal gene activation. Based on these findings, we propose that distinct HDACs play positive or negative roles in the control of cardiac growth by regulating opposing sets of target genes via their interactions with different sets of transcription factors.
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PMID:Dual roles of histone deacetylases in the control of cardiac growth. 1517 Dec 51

Histone proteins are essential for chromatin formation, and histone gene expression is coupled to DNA synthesis. In metazoans, the histone RNA binding protein HBP/SLBP is involved in post-transcriptional control of histone gene expression. In vitro assays have demonstrated that human HBP/SLBP is involved in histone mRNA 3' end formation and translation. We have inhibited human HBP/SLBP expression by RNA interference to determine its function during the mitotic cell cycle. Inhibition of HBP/SLBP expression resulted in the inhibition of histone gene expression and DNA synthesis, the inhibition of cell cycle progression in S phase and the inhibition of cell proliferation. These findings indicate that human HBP/SLBP is essential for the coordinate synthesis of DNA and histone proteins and is required for progression through the cell division cycle.
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PMID:The human histone gene expression regulator HBP/SLBP is required for histone and DNA synthesis, cell cycle progression and cell proliferation in mitotic cells. 1554 20

Histone proteins are essential components of eukaryotic chromosomes. In metazoans, they are produced from the so-called replication-dependent histone genes. The biogenesis of histones is tightly coupled to DNA replication in a stoichiometric manner because an excess of histones is highly toxic for the cell. Therefore, a strict cell cycle-regulation of critical factors required for histone expression ensures exclusive S-phase expression. This review focuses on the molecular mechanisms responsible for such a fine expression regulation. Among these, a large part will be dedicated to post-transcriptional events occurring on histone mRNA, like histone mRNA 3' end processing, nucleo-cytoplasmic mRNA export, translation and mRNA degradation. Many factors are involved, including an RNA-binding protein called HBP, also called SLBP (for hairpin- or stem-loop-binding protein) that binds to a conserved hairpin located in the 3' UTR part of histone mRNA. HBP plays a pivotal role in the expression of histone genes since it is necessary for most of the steps of histone mRNA metabolism in the cell. Moreover, the strict S-phase expression pattern of histones is achieved through a fine cell cycle-regulation of HBP. A large part of the discussion will be centered on the critical role of HBP in histone biogenesis.
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PMID:Expression of metazoan replication-dependent histone genes. 1616 92

Epidemiological studies demonstrated that even in the absence of other risk factors (e.g. diabetes, hypertension, hyperhomocysteinemia, hypercholesterolemia), advanced age itself significantly increases cardiovascular morbidity by enhancing vascular oxidative stress and inflammation. Because the population in the Western world is rapidly aging, there is a substantial need for pharmacological interventions that delay the functional decline of the cardiovascular system. Resveratrol is an atoxic phytoestrogen found in more than 70 plants including grapevine and berries. Recent data suggest that nutritional intake of resveratrol and other polyphenol compounds may contribute to the "French paradox", the unexpectedly low cardiovascular morbidity in the Mediterranean population. There is increasing evidence that resveratrol exerts multifaceted anti-oxidant and/or anti-inflammatory effects in various disease models. Importantly, resveratrol was reported to slow aging and increase lifespan in simple organisms and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to activate NAD-dependent histone deacetylases (sirtuins), which may contribute to its anti-aging effects. This review focuses on the role of oxidative stress and inflammation in cardiovascular dysfunction in aging, and on emerging anti-aging therapeutic strategies offered by resveratrol and other polyphenol compounds.
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PMID:Vascular dysfunction in aging: potential effects of resveratrol, an anti-inflammatory phytoestrogen. 1661 Oct 80


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