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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis is probably caused by multiple interacting factors such as disturbed lipid metabolism; endothelial cell damage, leading to platelet aggregation and monocyte invasion with the release of mitogenic factors; and disorders of fibrin balance, leading to persisting fibrin deposits. Deficient fibrinolysis may (1) predispose to fibrin deposition and contribute to the pathogenesis of atherosclerosis and (2) contribute to occlusive thrombus formation on fissured plaque, provoking atherothrombosis. Prospective epidemiologic studies have so far not provided definitive evidence that deficient fibrinolysis constitutes a significant risk factor for the development of atherosclerosis. Two recent findings, however, strongly suggest a contribution: (1) Increased lipoprotein(a) levels that reduce tissue-type plasminogen activator (t-PA)-mediated clot lysis are a clear risk factor for atherosclerosis; and (2) increased plasminogen activator inhibitor-1 (PAI-1) levels in patients with disturbed glucose tolerance predispose to an accelerated development of atherosclerotic disease. However, deficient fibrinolysis constitutes a risk factor for the development of thrombotic complications (acute myocardial infarction) in patients with coronary artery disease. The potential role of deficient fibrinolysis in the pathogenesis of atherosclerosis and of atherothrombosis suggests that drugs normalizing deficient endogenous fibrinolysis by either reducing PAI-1 synthesis or by stimulating endogenous t-PA synthesis may be of clinical value. Although regulation of the gene expression of PAI-1 and t-PA is presently under active investigation, no potent specific and safe agents to downregulate PAI-1 or to upregulate t-PA have as yet been identified. Retinoic acid appears to be a specific inducer of t-PA synthesis in human endothelial cells in culture and may constitute a model for the development of drugs that stimulate endogenous t-PA synthesis.
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PMID:On the role of coagulation and fibrinolysis in atherosclerosis. 134 93

Dedifferentiation and proliferation of vascular smooth muscle cells (VSMCs) are important features of atherosclerosis. The molecular mechanisms are largely unclear; however, protein kinase C (PKC) is a key enzyme in the intracellular signaling pathways that mediate this process. We studied the activity and immunoreactivity of PKC-alpha in primary cultures of VSMCs from rat aortas under different conditions of growth and differentiation. PKC-alpha was determined under the following conditions: (1) during the growth phase and after confluence of cultured (passages 1 through 3) VSMCs, (2) before and after induction of differentiation in VSMCs by retinoic acid, and (3) in primary cultures of VSMCs from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats during early passages. PKC activity was measured by in vitro substrate phosphorylation. PKC-alpha immunoreactivity was assessed by Western blot using specific polyclonal antibodies and by immunostaining with confocal microscopy. Cell proliferation was measured by direct count. The cell phenotype was characterized by immunostaining and Western blot for alpha-actin and desmin. PKC-alpha expression and PKC activity during VSMC growth showed a decrease during rapid growth and an increase in confluent cells. This pattern was associated with the respective changes in cell differentiation. Retinoic acid induced an increase in PKC-alpha expression together with a more differentiated phenotype. Subcultured, rapidly growing VSMCs from SHR showed a decreased PKC-alpha expression compared with cells from WKY rats. To establish cause and effect, we next microinjected either PKC-alpha or inactivated material directly into dedifferentiated cells. We found that cells injected with active PKC-alpha expressed increased amounts of actin compared with control cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differentiation of vascular smooth muscle cells and the regulation of protein kinase C-alpha. 800 Dec 76

The homozygous mutant mouse staggerer (RORa(sg)/RORa(sg)), was initially described as ataxic, due to the presence of massive neurodegeneration in the cerebellum [Science 136 (1962) 610]. The identification of the widely expressed Retinoic acid receptor-related Orphan Receptor, NR1F1 (RORalpha) gene as the site of mutation in the staggerer mouse has led to great progress in understanding the molecular basis of its phenotype in recent years [Nature 379 (1996) 736]. RORalpha is a transcription factor, belonging to the nuclear receptor superfamily, for which no natural ligand has yet been identified. Mice engineered for the disruption of the gene encoding RORalpha display the same cerebellar atrophic phenotype as the staggerer mouse [Proc. Natl. Acad. Sci. USA 95 (1998) 3960]. More recently, it has been shown that the mutation is semi-dominant, as heterozygous animals display an increased loss of Purkinje cells with age. Furthermore, a number of additional phenotypes outside the nervous system have recently been identified. These include a greater susceptibility to atherosclerosis [Circulation 15 (1998) 2738], immunodeficiencies linked to the overexpression of inflammatory cytokines [J. Neurochem. 58 (1992) 192], abnormalities in the formation and maintenance of bone tissue [Proc. Natl. Acad. Sci. USA 97 (2000) 9197] and changes in muscle differentiation [Nucleic Acids Res. 27 (1999) 411]. Thus, RORalpha has been directly linked to a number of age-related pathologies of great medical interest.
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PMID:Age-related phenotypes in the staggerer mouse expand the RORalpha nuclear receptor's role beyond the cerebellum. 1185 Jan 16

Retinoic acid receptors are ligand-regulated transcription factors belonging to the nuclear receptor superfamily, which comprises 49 members in the human genome. all-trans retinoic acid and 9-cis retinoic acid receptors (RARs and RXRs) are each encoded by three distinct genes and several isoforms arise from alternative splicing and the use of different promoters. While RXRs are promiscuous dimerization partners of several other nuclear receptors, RARs are active, in-vivo, when associated to RXRs. Retinoids are therefore regulators of multiple physiological processes, from embryogenesis to metabolism. Different combinations of RXR:RAR heterodimers occur as a function of their tissue-specific expression and their activity is mostly conditioned by the activation status of RAR. These heterodimers are defined as non permissive heterodimers, in opposition to permissive dimers whose transcriptional activity may be modulated through RXR and its dimerization partner. The transcriptional activity of these dimers also relies on their ability to recruit nuclear coactivators and corepressors, which function as multi proteic complexes harboring several enzymatic activities (acetylases, kinases). The structure of the ligand bound to the RAR moiety of the dimer, as well as the nature of the DNA sequence to which dimers are bound, dictate the relative affinity of dimers for coactivators and thus its overall transcriptional activity. RARs are also able to repress the activity of unrelated transcription factors such as AP1 and NF-kappa-B, and therefore have potent anti proliferative and anti inflammatory properties. This review summarizes our current view of molecular mechanisms governing these various activities and emphasizes the need for a detailed understanding of how retinoids may dictate transactivating and transrepressive properties of RARs and RXRs, which may be considered as highly valuable therapeutic targets in many diseases such as cancer, skin hyperproliferation and metabolical disorders (diabetes, atherosclerosis etc).
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PMID:Molecular basis for designing selective modulators of retinoic acid receptor transcriptional activities. 1247 96

Retinoic acid receptor-related Orphan Receptor alpha (RORalpha) is a member of the nuclear hormone receptor superfamily. RORalpha has long been considered as a constitutive activator of transcription in the absence of exogenous ligand; however, cholesterol has recently been identified as a natural ligand of RORalpha. The spontaneous staggerer (sg/sg) mutation is a deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of RORalpha activity. The homozygous Rora(sg/sg) mutant mouse, of which the most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes, including several vascular ones; in particular, dysfunction of smooth muscle cells and enhanced susceptibility to atherosclerosis. Moreover, RORalpha appears to participate in the regulation of plasma cholesterol levels, and has been shown to positively regulate apolipoprotein (apo)A-I and apoC-III gene expression. Yet its activity is regulated by cholesterol itself, making RORalpha an intracellular cholesterol target.
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PMID:The "CholesteROR" protective pathway in the vascular system. 1475 13

Retinoic acid modulates cell growth and differentiation of the vascular system. Vascular endothelial growth factor (VEGF) is known as a vascular permeability factor and a potent mitogen for vascular endothelial cells. In the present study, we investigated whether retinoic acid induces VEGF release in aortic smooth muscle A10 cells and if so, the mechanism of VEGF release. Retinoic acid stimulated VEGF release dose-dependently over the range 0.1 nM-0.1 microM. The retinoic acid-stimulated VEGF release was significantly reduced by actinomycin D. Retinoic acid induced the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase but not p38 MAP kinase or stress-activated protein kinase/c-Jun N-terminal kinase among the MAP kinase superfamily. This effect of retinoic acid was dose-dependent (30 nM-5 microM) and the maximum effect was observed at 0.3 microM. The retinoic acid-stimulated release of VEGF was significantly reduced by PD98059 and U0126, specific MEK inhibitors, which attenuated the retinoic acid-induced phosphorylation of p44/p42 MAP kinase. These results strongly suggest that retinoic acid stimulates the release of VEGF in a p44/p42 MAP kinase-dependent manner in aortic smooth muscle cells.
Atherosclerosis 2004 Aug
PMID:Possible involvement of p44/p42 MAP kinase in retinoic acid-stimulated vascular endothelial growth factor release in aortic smooth muscle cells. 1526 80

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

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

Isotretinoin treatment alters the plasma lipid levels but the mechanisms and the effects on the metabolism of triglyceride-rich lipoproteins such as chylomicrons and very-low-density lipoproteins remain unclear. We investigated the effect of isotretinoin on the plasma kinetics of emulsion models of triglyceride-rich lipoproteins and the lipid profile. Ten patients with acne were treated with 0.8 mg/kg of isotretinoin over 4 weeks for comparison with non-treated acne patients. In both groups the plasma kinetic study of a triglyceride-rich emulsion double-labeled with 14C-cholesterol oleate and 3H-triolein was performed after intravenous injection of the emulsion and radioactive counting in plasma samples collected over 60 min. Patients using isotretinoin showed decreased removal from the plasma of the 3H-triglyceride (median 0.019 min-1 TG) compared with controls (median 0.044 min-1, P=0.007), and the removal of the emulsion 14C-cholesterol oleate also tended to be decreased (treatment: 0.011 min-1; controls: 0.024 min-1, P=0.06). The values of total and LDL cholesterol and triglycerides were increased post-treatment (P<0.03). In conclusion, while increasing the fasting plasma concentration of VLDL and LDL, which are traditional risk factors for atherosclerosis, isotretinoin treatment also slows down the metabolism of triglyceride-rich lipoproteins such as chylomicrons, as tested by the emulsion model, an effect that is also increasingly recognized as atherogenic.
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PMID:Effects of isotretinoin on the metabolism of triglyceride-rich lipoproteins and on the lipid profile in patients with acne. 1642 99


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