Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We recently identified a novel gene that is negatively regulated by extracellular calcium concentration with higher levels of transcripts in hypertensive animals (SHR). We named this gene HCaRG (Hypertension-related, Calcium-Regulated Gene). In this work we report the chromosomal localization of the HCaRG gene among different species. We identified a BglII RFLP between BN.lx and SHR rats. We then analysed the strain distribution pattern of this RFLP in 31 RIS, originating from BN.lx and SHR rats, and compared it to the segregation of 475 markers localized in the rat genetic map. Hcarg localizes to the rat chromosome 7 between the markers Mit3 and Mit4. This region is homologous to human chromosome 8q21-24. We identified three clones in Genbank that contain the sequence of HCaRG. It was therefore possible to narrow down the localization of human HCaRG to chromosome 8q24.3. Furthermore, a suggestive localization of mouse Hcarg based on conservation of linkage between human and mouse is on chromosome 15. We previously identified a putative calcium-binding motif (EF-Hand) and a nuclear receptor-binding domain (LxxLL) in the rat sequence of the HCaRG protein. Sequence comparison between five different species showed that these domains are highly conserved. Furthermore, a search of ESTs in Genbank for homologous sequences showed that HCaRG is expressed only in eukaryotes, particularly in mammals.
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PMID:Chromosomal mapping of HCaRG, a novel hypertension-related, calcium-regulated gene. 1187 61

Traditionally, the role of aldosterone in heart failure was thought to be a result of its effects on epithelial cells where it induces sodium reabsorption and potassium excretion with subsequent haemodynamic effects from intravascular volume expansion. On this basis, spironolactone, a non-selective aldosterone antagonist, has been used for the treatment of congestive heart failure to block aldosterone-mediated effects in epithelial cells. The Randomized Aldactone Evaluation Study (RALES), in which spironolactone was added to existing therapy in patients with heart failure, showed a significant reduction in morbidity and mortality. These results suggest that the role of aldosterone in the pathophysiology of cardiovascular disease may be more complex than previously recognised. There now is extensive experimental and growing clinical evidence for an important physiological role for aldosterone in the pathology of cardiac and renal disease. Classical effects of aldosterone are mediated via its nuclear receptor. Novel non-epithelial effects of aldosterone are mediated via a second messenger system, which involves activation of the sodium/hydrogen antiporter. These effects of aldosterone have been demonstrated in the kidney, vascular smooth muscle cell and leukocytes, and in the regulation of rapid corticotropin suppression. It has been hypothesised that cardiac damage induced by aldosterone is independent of the presence of hypertension. In support of this, experimental evidence demonstrates that cardiovascular damage induced by aldosterone can be prevented by administration of a selective mineralocorticoid receptor antagonist. These findings suggest the dissociation between cardiovascular lesions and high blood pressure, and highlight the importance of aldosterone in the pathological changes.
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PMID:Rationale for the use of aldosterone antagonists in congestive heart failure. 1192 27

In the last few years there has been an explosion of research that has improved our understanding of the pathogenesis of Type 2 diabetes mellitus (DM-2) and has led to the development of new oral antidiabetic drugs. Thiazolidinediones (TZDs) are the newest of these antidiabetic agents. TZDs are insulin sensitisers that depend on the presence of insulin for their action. They target insulin resistance, which is thought to play a central role in DM-2 and the associated metabolic syndrome characterised by central obesity, hypertension, dyslipidemia and hypercoagulability, all leading to increased cardiovascular morbidity and mortality. As a result, TZDs have the potential to improve other conditions associated with the metabolic syndrome, in addition to their glycaemic action. TZDs act by activating peroxisome proliferator-activated receptor (PPAR) phi a nuclear receptor implicated not only in lipid and glucose metabolism but other physiological functions as well. TZDs may have wide clinical applications beyond DM-2, as they can potentially be used to treat other conditions associated with insulin resistance and PPAR-phi receptors, such as impaired glucose tolerance, polycystic ovarian syndrome and HIV lipodystrophy.
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PMID:Thiazolidinediones in the treatment of type 2 diabetes. 1199 32

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor isoforms, including PPARgamma, PPARalpha, and PPARdelta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors increasing the rate of transcription initiation. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Natural ligands for the PPARs include fatty acids and eicosanoids. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, are effective in the treatment of dyslipidemia and diabetes. Use of selective ligands led to the discovery of additional potential roles for the PPARs in pathological states, including atherosclerosis, inflammation, and hypertension. This review provides an overview of the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.
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PMID:Physiological and therapeutic roles of peroxisome proliferator-activated receptors. 1207 20

Several cardiovascular risk factors (dyslipidaemia, hypertension, glucose intolerance, hypercoagulability, obesity, hyperinsulinaemia and low-grade inflammation) cluster in the insulin resistance syndrome. Treatment of these individual risk factors reduces cardiovascular complications. However, targeting the underlying pathophysiological mechanisms of the insulin resistance syndrome is a more rational treatment strategy to further improve cardiovascular outcome. Our understanding of the so-called cardiovascular dysmetabolic syndrome has been improved by the discovery of nuclear peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. As transcription factors, PPARs regulate the expression of numerous genes and affect glycaemic control, lipid metabolism, vascular tone and inflammation. Activation of the subtype PPAR-gamma improves insulin sensitivity. Expression of PPAR-gamma is present in several cell types involved in the process of atherosclerosis. Thus, modulation of PPAR-gamma activity is an interesting therapeutic approach to reduce cardiovascular events. Thiazolidinediones are PPAR-gamma agonists and constitute a new class of pharmacological agents for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Two such compounds are currently available for clinical use: rosiglitazone and pioglitazone. Thiazolidinediones improve insulin sensitivity and glycaemic control in patients with type 2 diabetes. In addition, improvement in endothelial function, a decrease in inflammatory conditions, a decrease in plasma levels of free fatty acids and lower blood pressure have been observed, which may have important beneficial effects on the vasculature. Several questions remain to be answered about PPAR-gamma agonists, particularly with respect to the role of PPAR-gamma in vascular pathophysiology. More needs to be known about the adverse effects of thiazolidinediones, such as hepatotoxicity, increased low-density lipoprotein cholesterol levels and increased oedema. The paradox of adipocyte differentiation with weight gain concurring with the insulin-sensitising effect of thiazolidinediones is not completely understood. The decrease in blood pressure induced by thiazolidinedione treatment seems incompatible with an increase in the plasma volume, and the discrepancy between the stimulation of the expression of CD36 and the antiatherogenic effects of the thiazolidinediones also needs further explanation. Long-term clinical trials of thiazolidinediones with cardiovascular endpoints are currently in progress. In conclusion, studying the effects of thiazolidinediones may shed more light on the mechanisms involved in the insulin resistance syndrome. Furthermore, thiazolidinediones could have specific, direct effects on processes involved in the development of vascular abnormalities.
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PMID:Metabolic and additional vascular effects of thiazolidinediones. 1209 15

The insulin resistance syndrome, a cluster of metabolic abnormalities involving dyslipidemia, hypertension, diabetes, impaired glucose tolerance, and hypercoagulability, carries an increased risk of atherosclerosis. Although interventions targeting elements of this syndrome have dramatically reduced cardiovascular risk, the impact of glucose-lowering has been more disappointing. Thiazolidinediones (TZDs) are a new class of insulin-sensitizing agents that activate the nuclear receptor peroxisome proliferator-activated receptor-g. TZDs may improve not only glucose levels but also other metabolic parameters associated with insulin resistance. The TZD data are reviewed, with a focus on their potential cardiovascular effects.
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PMID:Insulin resistance, diabetes, and atherosclerosis: thiazolidinediones as therapeutic interventions. 1237 75

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which upon activation with various natural and synthetic ligands, stimulates the transcription of genes responsible for growth and differentiation of adipocytes. Furthermore, PPAR gamma is the receptor for the insulin-sensitizing thiazolidinediones, which are commonly used for the treatment of type 2 diabetes. Rare inactivating mutations of the gene encoding PPAR gamma are associated with insulin resistance type 2 diabetes, and hypertension, whereas a rare gain of function mutation causes extreme obesity. A common polymorphism (Pro12Ala) of the adipose tissue-specific gamma 2 isoform is associated with increased insulin sensitivity and decreased risk of developing type 2 diabetes. These findings indicate a central role of PPAR gamma in fat cell biology and in the pathophysiology of obesity, diabetes, and insulin resistance.
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PMID:The role of peroxisome proliferator-activated receptor gamma in diabetes and obesity. 1264 37

We previously reported a syndrome of severe hyperinsulinemia and early-onset hypertension in three patients with dominant-negative mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-gamma. We now report the results of further detailed pathophysiological evaluation of these subjects, the identification of affected prepubertal children within one of the original families, and the effects of thiazolidinedione therapy in two subjects. These studies 1) definitively demonstrate the presence of severe peripheral and hepatic insulin resistance in the affected subjects; 2) describe a stereotyped pattern of partial lipodystrophy associated with all the features of the metabolic syndrome and nonalcoholic steatohepatitis; 3) document abnormalities in the in vivo function of remaining adipose tissue, including the inability of subcutaneous abdominal adipose tissue to trap and store free fatty acids postprandially and the presence of very low circulating levels of adiponectin; 4) document the presence of severe hyperinsulinemia in prepubertal carriers of the proline-467-leucine (P467L) PPAR-gamma mutation; 5) provide the first direct evidence of cellular resistance to PPAR-gamma agonists in mononuclear cells derived from the patients; and 6) report on the metabolic response to thiazolidinedione therapy in two affected subjects. Although the condition is rare, the study of humans with dominant-negative mutations in PPAR-gamma can provide important insight into the roles of this nuclear receptor in human metabolism.
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PMID:Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. 1266 60

By the end of this decade, it has been estimated that between 200 million and 300 million people worldwide will meet World Health Organization diagnostic criteria for diabetes mellitus. This epidemic of predominantly type 2 diabetes has largely been mediated by our shift toward a more sedentary lifestyle predisposing to obesity and insulin resistance. Affected individuals can also exhibit an array of associated undesirable traits such as hypertension, dyslipidemia, and hypercoagulability, leading to morbidity and mortality from atherosclerotic vascular disease. The coexistence of several of these traits with insulin resistance constitutes the metabolic syndrome. Accordingly, improving insulin sensitivity in this group, and thereby potentially ameliorating the excess vascular risk, is a primary goal of treatment. Recent interest has focused on the thiazolidinediones, a novel class of antidiabetic agents, which act as insulin sensitizers and, therefore, potentially target the underlying metabolic disturbance. These agents are high-affinity ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma, and a large body of in vitro and in vivo data has evolved to support their increasing clinical use. Importantly, clinical and laboratory findings in human subjects harboring natural mutations and polymorphisms within the receptor have provided additional insights. Here, we focus on the consequences of inherited variation in the human peroxisome proliferator-activated receptor gamma gene, linking this receptor to disordered glucose homeostasis, adipogenesis, lipid metabolism, and blood pressure regulation. These studies provide further support for the future development of more selective receptor modulators, targeting specific pathways to ameliorate facets of the metabolic syndrome.
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PMID:The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation. 1278 36

The hypothesis that cross-talk between membrane-active beta-adrenergic agonists and estrogens includes beta-adrenergic modulation of estrogen receptor (ER)-regulated gene expression was investigated. Vascular smooth muscle-derived A7r5 cells were transfected with an ERalpha expression plasmid (pCR3.1-hERalpha), the estrogen response element (ERE)-linked reporter pERE-E1b-luciferase (ERE-Luc), and pCMV-beta-galactosidase using a lysine-conjugated adenovirus transfection method. Hormone or agonist treatment and harvest followed 6 hours and 24 hours later, respectively. Treatment with 17beta-estradiol (E(2), 1 nmol/L) significantly stimulated ERE-Luc activity. Isoproterenol (10-9 to 10-6 mol/L) treatment alone did not stimulate ERE-Luc activity. Cotreatment with both E(2) and isoproterenol resulted in complete inhibition of E(2)-stimulated ERE-Luc activity. This isoproterenol effect was prevented by the beta-adrenergic antagonist propanolol (10-6 mol/L). Adrenomedullin treatment in these cells (1-50 nmol/L) did not inhibit ER/ERE-Luc activity, whether in the presence or absence of E(2). Moreover, isoproterenol did not affect vitamin D-stimulated VDRE-Luc expression, indicating that the inhibitory effect of isoproterenol on E(2)-directed ERE-Luc expression is specific among nuclear transcription factor receptors. Moreover, in MCF-7 breast cancer cells, there was no effect of isoproterenol on ER/ERE-directed transcription in the absence or presence of E(2), demonstrating tissue specificity of this isoproterenol effect. These studies demonstrate cross-talk between the beta-adrenergic agonist isoproterenol and ER-directed reporter gene expression in A7r5 cells. Furthermore, this cross-talk is specific with respect to agonist, nuclear receptor species, and cell type. These observations may have important implications both for the use of beta-adrenergic agents to treat hypertension and for possible gender-related differences in cardiovascular regulation.
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PMID:Cross-talk between beta-adrenergic stimulation and estrogen receptors: isoproterenol inhibits 17beta-estradiol-induced gene transcription in A7r5 cells. 1288 32


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