Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since elevated concentrations of plasma high density lipoprotein (HDL) and its major apolipoprotein (apo), apoA-I, confer protection against atherosclerosis, considerable research efforts have focussed on the identification of factors regulating apoA-I gene expression in an attempt to increase its production. Nuclear receptors are interesting candidates because they are transcription factors whose activity is ligand-dependent. In the present study we identified the orphan receptor RORalpha1 as an activator of apoA-I gene transcription. In apoA-I-expressing intestinal Caco-2 cells, overexpression of the RORalpha1, but not the RORalpha2 or RORalpha3 isoforms, increased rat apoA-I gene transcription. Deletion and site-directed mutagenesis experiments identified a functional ROR-responsive element (RORE) in the rat and mouse apoA-I gene promoters, which overlaps with the TATA box. Gel shift experiments indicated that this RORE binds the RORalpha1 isoform, but not the RORalpha2 or RORalpha3 isoforms. Furthermore, compared with wild type mice, apoA-I mRNA levels were significantly lower in small intestines of staggerer mice homozygous for a deletion in the RORalpha gene. In addition, reverse transcriptase-polymerase chain reaction analysis revealed the expression of RORalpha in small intestinal epithelium and in Caco-2 cells. These data indicate a novel, physiological role for RORalpha1 in the regulation of genes involved in lipid and lipoprotein metabolism and possibly in the development of metabolic diseases, such as atherosclerosis.
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PMID:Transcriptional regulation of apolipoprotein A-I gene expression by the nuclear receptor RORalpha. 927 89

The peroxisome proliferator-activated receptor gamma (PPARgamma) quickly evolved over the last decade from a new orphan receptor to one of the best characterized nuclear receptors. This fast pace in PPARgamma research was triggered by two main discoveries. Firstly, that PPARgamma was shown to have a key role in adipogenesis and be a master controller of the "thrifty gene response" leading to efficient energy storage. Secondly, the discovery that its synthetic ligands, the thiazolidinediones, are promising insulin sensitizing drugs, which are currently being developed for the treatment of Type II (non-insulin-dependent) diabetes mellitus. More recently this nuclear receptor emerged from a role limited to metabolism (diabetes and obesity) to a power player in general transcriptional control of numerous cellular processes, with implications in cell cycle control, carcinogenesis, inflammation, atherosclerosis and immunomodulation. This widened role of PPARgamma will certainly initiate a new flurry of research, which will not only refine our current often partial knowledge of PPARgamma but more importantly also establish that this receptor has a definite role as a primary link adapting cellular, tissue and whole body homeostasis to energy stores.
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PMID:PPARgamma, the ultimate thrifty gene. 1044 13

Using novel synthetic radioligands, we have discovered receptors for the recently paired apelin (APJ orphan receptor), ghrelin (GHS orphan receptor), and urotensin II (orphan GPR14) in the human cardiovascular system and determined their anatomical localisation. In addition, we have established functional vasoactive properties for these three peptides as potential vasoconstrictor/vasodilator mediators and provided evidence for alteration of receptor density in cardiovascular disease. We find that receptors for apelin, ghrelin, and urotensin II are widely distributed in human cardiovascular tissue, suggesting perhaps vasoactive roles for these peptides in human vascular physiology and a potential role in pathophysiology. Apelin and urotensin II are potent vasoconstrictors with low efficacy, consistent with their low receptor density. Ghrelin receptor density was increased (approximately three- to fourfold) with atherosclerosis of coronary artery disease and accelerated atherosclerosis of saphenous vein grafts, compared with normal vessels, highlighting a potentially beneficial role for this novel vasodilator peptide in human vascular disease. Our approach has demonstrated one successful strategy for translating genetic information encoding recently paired orphan receptor ligands into discovery of function. This study has the advantage of focussing on the actual disease processes, which allow the more precise identification of novel therapeutic targets.
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PMID:Discovery of recently adopted orphan receptors for apelin, urotensin II, and ghrelin identified using novel radioligands and functional role in the human cardiovascular system. 1205 41

Urotensin-II (U-II), a peptide isolated from the urophysis of teleost fish 35 years ago, is the endogenous ligand of the mammalian orphan receptor GPR14/SENR. Recently, human homologues of both the receptor (UT-II) and the peptide (hU-II) have been discovered. Following de-orphanization, hU-II was declared the 'new endothelin' as initial studies suggested similarities between the peptides, and in isolated arteries of cynomolgus monkey U-II was a more potent constrictor than endothelin-1 (ET-1), with equal efficacy. However, effects of U-II in vascular tissue from other mammalian species are variable and although potent, U-II exhibits a lesser maximal response than ET-1. In contrast, in humans U-II has emerged as a ubiquitious constrictor of both arteries and veins in vitro and elicits a reduction in blood flow in the forearm and skin microcirculation in vivo. In addition to direct vasoconstrictor activity on smooth muscle receptors, endothelium-dependent U-II-mediated vasodilatation has also been observed. Non-vascular, peripheral actions of U-II include potent inotropy and airway smooth muscle constriction and U-II and its receptor are present throughout rat brain implying a possible neurotransmitter or neuromodulatory role in the central nervous system. U-II is proposed to contribute to human diseases including atherosclerosis, cardiac hypertrophy, pulmonary hypertension and tumour growth. The development of selective receptor antagonists should help to clarify the relative importance of hU-II as a multifunctional peptide in mammalian systems and its role in disease. What is clear is that U-II is emerging as a new and potentially important mammalian transmitter.
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PMID:Is urotensin-II the new endothelin? 1238 71

The human estrogen-related receptor alpha1 (ERR alpha 1) is a member of an orphan receptor family closely related to the estrogen receptor. It has been demonstrated that estrogen modulates endothelial nitric oxide synthase (eNOS) expression through the estrogen receptor in endothelial cells. However, little is known about the relationship between ERR alpha 1 and eNOS. In this study, we show that ERR alpha 1 activates the estrogen response element (ERE) and eNOS promoter-dependent luciferase activity in COS-7 cells and bovine pulmonary artery endothelial cells. The endogenous ligand for ERR alpha 1 has not been identified, but we show that these actions are dependent on serum constituents because ERR alpha 1 fails to stimulate eNOS promoter-dependent luciferase activity in charcoal-treated serum. Furthermore, through the use of truncated eNOS promoter luciferase constructs, we demonstrate that the activation of eNOS transcription by ERR alpha 1 is mediated via three regions: base pairs -1001 to -743, base pairs -743 to -265, and downstream from base pair -265 on the eNOS promoter. In addition, ERR alpha 1 up-regulates eNOS mRNA and protein expression and stimulates eNOS activity in bovine pulmonary artery endothelial cells. These results suggest that ERR alpha 1 has a potential role in the regulation of eNOS expression and may stimulate NO production by endothelial cells, which may in turn result in a protective effect against atherosclerosis.
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PMID:Estrogen-related receptor alpha 1 up-regulates endothelial nitric oxide synthase expression. 1461 Feb 83

Retinoic acid-receptor-related orphan receptor (ROR) alpha is a nuclear receptor involved in many pathophysiological processes such as cerebellar ataxia, inflammation, atherosclerosis and angiogenesis. In the present study we first demonstrate that hypoxia increases the amount of Rora transcripts in a wide panel of cell lines derived from diverse tissues. In addition, we identified a functional promoter sequence upstream of the first exon of the human Rora gene, spanning -487 and -45 from the translation initiation site of RORalpha1. When cloned in a luciferase reporter vector, this sequence allowed the efficient transcription of the luciferase gene in several cell lines. Interestingly, the activity of the Rora promoter was enhanced by hypoxia in HepG2 human hepatoma cells, and this effect was dependent on an HRE (hypoxia response element) spanning from -229 to -225. Using electrophoretic-mobility-shift assays, we showed that HIF-1 (hypoxia-inducible factor 1), which plays a key role in the transcriptional response to hypoxia, bound to this HRE. Overexpression of HIF-1alpha increased the activity of the Rora promoter through the HRE. Overexpression of a dominant-negative form of HIF-1alpha producing transcriptionally inactive HIF-1alpha/HIF-1beta dimers abolished hypoxic activation of the Rora promoter. This indicated that HIF-1 is involved in the response of RORalpha to hypoxia. Taken together, our data reveal Rora as a new HIF-1 target gene. This illustrates, at the molecular level, the existence of cross-talk between signalling pathways mediated by HIF-1 and those mediated by nuclear receptors.
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PMID:The gene encoding human retinoic acid-receptor-related orphan receptor alpha is a target for hypoxia-inducible factor 1. 1527 Jul 19

Urotensin II (UII) has been found to be a potent vasoactive peptide in humans and in a number of relevant animal models of cardiovascular disease such as the mouse, rat and other non-human primates. This peptide with structural homology to somatostatin was first isolated from the urophysis of fish and was recently found to bind to an orphan receptor in mouse and human. Initially found to have potent vasoconstrictive activities in a variety of vessels from diverse species, it has also been shown to exert vasodilatation in certain vessels in the rat and human by various endothelium-dependent mechanisms. The various vasoactive properties of UII suggest that the peptide may have a physiological role in maintaining vascular tone and therefore may have a role in the pathophysiology of a number of human diseases such as heart failure. Moreover, UII has also been implicated as a mitogen of vascular smooth muscle cells suggesting a deleterious role in atherosclerosis and coronary artery disease. In addition, there is evidence to demonstrate that UII has multiple metabolic effects on cholesterol metabolism, glycemic control and hypertension and therefore may be implicated in the development of insulin resistance and the metabolic syndrome.
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PMID:Urotensin II and cardiovascular diseases. 1547 47

Retinoic acid receptor-related orphan receptor-alpha (RORalpha) (NR1F1) is an orphan nuclear receptor with a potential role in metabolism. Previous studies have shown that RORalpha regulates transcription of the murine Apolipoprotein AI gene and human Apolipoprotein CIII genes. In the present study, we present evidence that RORalpha also induces transcription of the human Apolipoprotein AV gene, a recently identified apolipoprotein associated with triglyceride levels. Adenovirus-mediated overexpression of RORalpha increased the endogenous expression of ApoAV in HepG2 cells and RORalpha also enhanced the activity of an ApoAV promoter construct in transiently transfected HepG2 cells. Deletion and mutation studies identified three AGGTCA motifs in the ApoAV promoter that mediate RORalpha transactivation, one of which overlaps with a previously identified binding site for PPARalpha. Together, these results suggest a novel mechanism whereby RORalpha modulates lipid metabolism and implies RORalpha as a potential target for the treatment of dyslipidemia and atherosclerosis.
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PMID:Identification of the human ApoAV gene as a novel RORalpha target gene. 1578 Dec 55

Fibrinogen is a plasma protein synthesized by the liver. It is composed of three chains (alpha, beta, gamma). In addition to its main function as a coagulation factor, this acute phase protein is also a risk marker for atherosclerosis. Retinoic acid receptor-related orphan receptor (ROR)alpha is a nuclear receptor modulating physiopathological processes such as cerebellar ataxia, inflammation, atherosclerosis, and angiogenesis. In this study, we identified RORalpha as a regulator of fibrinogen-beta gene expression in human hepatoma cells and in mouse liver. A putative RORalpha response element (RORE) was identified in the human fibrinogen-beta promoter. EMSA showed that RORalpha binds specifically to this RORE, and cotransfection experiments in HepG2 hepatoma cells indicated that this RORE confers RORalpha-dependent transcriptional activation to both the human fibrinogen-beta and the thymidine kinase promoters. Stable transfection experiments in HepG2 and Hep3B hepatoma cells demonstrated that overexpression of RORalpha specifically increases endogenous fibrinogen-beta mRNA levels. Chromatin immunoprecipitation experiments revealed that the fibrinogen-beta RORE is occupied by RORalpha in HepG2 cells. Thus, the human fibrinogen-beta gene is a direct target for RORalpha. Furthermore, fibrinogen-beta mRNA levels in liver and plasma fibrinogen concentrations are specifically decreased in staggerer mice, which are homozygous for a deletion invalidating the Rora gene. Taken together, these data add further evidence for an important role of RORalpha in the control of liver gene expression with potential pathophysiological consequences on coagulation and cardiovascular risk.
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PMID:The gene encoding fibrinogen-beta is a target for retinoic acid receptor-related orphan receptor alpha. 1594 50

Neuron-derived orphan receptor-1 (NOR-1) is a transcription factor over-expressed in human atherosclerotic plaques that is involved in vascular smooth muscle cell proliferation. The aim of this study was to analyze whether NOR-1 plays a role in vascular endothelial growth factor (VEGF) induced endothelial cell growth. VEGF induced an early and transient up-regulation of NOR-1 in human umbilical vein endothelial cells (HUVEC). NOR-1 up-regulation by VEGF is processed through VEGF receptor-2 (VEGFR-2) and involves different signaling pathways including increase in cytosolic Ca(2+), activation of protein kinase C and mitogen-activated protein kinase (MAPK) pathways (both extracellular-signaling regulated kinase [ERK] and p38 MAPK). VEGF induced CREB activation (phosphorylation in Ser(133)). In transfection assays, a dominant-negative of CREB inhibited NOR-1 promoter activity, while mutation of the three CRE sites in the NOR-1 promoter abolished VEGF-induced NOR-1 promoter activity. Antisense oligonucleotides against NOR-1 inhibited VEGF-induced endothelial cell growth (reduced DNA synthesis, and inhibited cell cycle progression and endothelial cell wound repair after mechanical injury). These results indicate that NOR-1 could be a key transcription factor regulating endothelial cell growth induced by VEGF.
Atherosclerosis 2006 Feb
PMID:NOR-1 is involved in VEGF-induced endothelial cell growth. 1594 8


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