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)

In experiments on modelling of cholesterol atherosclerosis in rabbits (1% cholesterol-rich diet during 2 month) it was determined changes of trypsin-like (TL), chymotrypsin-like (CHTL) and peptydilglutamilpeptidase (PGPG) proteasomal activity in tissues of aorta, heart and isolated blood leukocytes. It was shown that cholesterol-rich diet caused significant increase of TL (3.2 fold, P=0.003), PGPG (1.8 fold, P=0.003) proteasomal activity in aorta tissues, and PGPG activity (1.8-times, P=0.003) in myocardium. In isolated blood monocytes, the CHTL and PGPG activities were significantly increased (1.9 fold, P=0.05 and 11.6 fold, P=0.0001, respectively) and in PMN leucocytes the PGPG activity of proteasome was also significantly increased (1.8 fold, P=0.031). Proteasomal activity in lymphocytes during cholesterol atherosclerosis modelling had no significant changes. The data obtained indicate that alimentary hypercholesterolemia induces considerable changes of proteasomal activity in cardio-vascular system and blood cells that take part in atherogenesis.
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PMID:[Proteasome activity changes in the aorta, heart tissues, and blood leucocytes in modelling of cholesterol atherosclerosis]. 1830 25

Misfolded or damaged proteins are recognized intracellularly by protein quality mechanisms. These include chaperones and the ubiquitin-proteasome system, which aim at restoration of protein function and protein removal, respectively. A number of studies have outlined the functional significance of the ubiquitin-proteasome system for the heart and, as of recently, for the vascular system. This review summarizes these recent findings with a focus on atherosclerosis. In particular, this paper reflects on the viewpoint of atherosclerosis as a protein quality disease.
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PMID:Potential role of the ubiquitin-proteasome system in atherosclerosis: aspects of a protein quality disease. 1892 50

One of the major risk factors for ischemic disease is hyperlipidemia, which is mainly regulated by endogenous cholesterol synthesis in the liver and dietary absorption in the small intestine. In this study, we evaluated the vascular protective effects of a potent cholesterol absorption inhibitor, ezetimibe. ApoE-deficient mice were fed a chow or high-fat diet with or without ezetimibe (5mg/(kgday)) for 3 months. Co-treatment with ezetimibe significantly reduced plasma cholesterol (by 76%; from 1592 to 381mg/dL) and LDL cholesterol (by 78%; from 1515 to 319mg/dL), and increased HDL cholesterol (by 187%; from 16 to 46mg/dL) in high-fat diet mice. Consistently, a marked inhibitory effect of ezetimibe on the development of lipid-rich plaque was observed, as assessed by oil red O staining. Of importance, treatment with ezetimibe significantly improved endothelial dysfunction as assessed by the vasodilator response to acetylcholine, accompanied by inhibition of interleukin-6 mRNA and an increase in endothelial nitric oxide synthase (eNOS) mRNA in the aorta. Ezetimibe also suppressed oxidative stress and the ubiquitination-proteasome system in the aorta. Although changes in body weight and several tissue weights were similar in the groups with and without ezetimibe administration, only liver weight was significantly decreased in the ezetimibe-treated group. Interestingly, ezetimibe markedly inhibited lipid accumulation in the liver. Furthermore, ezetimibe increased the mRNA expression of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) synthase as a counteraction in the liver, but not in the aorta. Overall, ezetimibe significantly prevented atherosclerosis through not only lipid-lowering effects, but also other direct and/or indirect vascular protective actions in ApoE-deficient mice.
Atherosclerosis 2009 Mar
PMID:Vascular protective effects of ezetimibe in ApoE-deficient mice. 1860 52

Monocyte chemotactic protein-1 and interleukin-6 are important inflammatory cytokines, which have close relationships with atherosclerosis. Visfatin is a novel adipokine involved in regulation of inflammatory cytokines, however, associations of visfatin with cytokines (MCP-1, IL-6) in human umbilical vein endothelial cells are unclear. The aim of this study was to determine whether visfatin has effects on the expression of MCP-1 and IL-6 in human umbilical vein endothelial cells. Enzyme-linked immunosorbent assay were used for measuring MCP-1 and IL-6 production in human umbilical vein endothelial cells. Real-time quantitative reverse-transcription polymerase chain reaction was used for determining MCP-1 and IL-6 mRNA expression. For the pathway determination following inhibitors were used: wortmannin [phosphatiylinositol 3-kinase (PI3K)], SB203580 [p38 mitogen-activated protein kinase (MAPK)], PD98059 [extracellular signal-regulated kinase (ERK) 1/2)], JNK inhibitor II [c-Jun NH 2-terminal kinase (JNK)]. We demonstrated that visfatin could obviously upregulate secretion of MCP-1and IL-6 in a dose- and time-dependent manner in human umbilical vein endothelial cells. Visfatin-induced effects were diminished by SB203580, wortmannin, and PD98059. In summary, these results suggest that visfatin-induced MCP-1 and IL-6 production involve p38 MAPK, PI3K, and ERK 1/2 pathways in human umbilical vein endothelial cells as determined by inhibition with specific inhibitors.
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PMID:Visfatin stimulates production of monocyte chemotactic protein-1 and interleukin-6 in human vein umbilical endothelial cells. 1900 99

Recently more and more evidences have emerged about the oncogenic effect of type 2 diabetes and metabolic syndrome. Among these evidences epidemiological data are in first line. There is a causal relationship according to gender, ethnicity and geographic situation between different tumors and type 2 diabetes/metabolic syndrome as well. Supposed pathomechanisms are obesity, cytokines, secreted excessively in adipose tissue, permanent and postprandial hyperglycemia, hyperinsulinism and insulin resistance, other growth factors, like proinsulin, insulin like growth factor-1, reactive oxygen species, angiogenesis, inflammation, and the multiple effects of inflammatory cytokines. It proved to be evident that both peroxisome-proliferator-activated receptors and the regulatory ubiquitin proteasome system have significant role in insulin sensitivity and in co-ordinating cell proliferation and angiogenesis. These mechanisms in metabolic syndrome are risk factors towards atherosclerosis and cancer diseases as well. This newly emerged knowledge may open new pathways in treating and preventing the above-mentioned pathologic processes.
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PMID:[The metabolic syndrome and type-2 diabetes mellitus as conditions predisposing for malignant tumors]. 1907 51

The ubiquitin-proteasome system (UPS) plays a central role in intracellular protein degradation and regulates many cellular processes, including cell proliferation, inflammation, adaptation to stress, cell death, and the removal of damaged or misfolded proteins. Numerous studies have demonstrated that altered UPS function is involved in the pathogenesis of a wide range of cardiac diseases including hypertrophy and failure, myocardial ischemia, atherosclerosis, and diabetic cardiovascular disease. Impairment of proteasome function is a common feature of cardiac disease; however several studies have also demonstrated increased proteasome activity in models similar but not identical with those having decreased function. Recent studies have shown that use of proteasome inhibitors before or following production of the model of cardiac disease may confer cardioprotection under certain conditions.
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PMID:Targeting proteasomes for cardioprotection. 1909 37

Myocardin, a coactivator of serum response factor (SRF), plays a critical role in the differentiation of vascular smooth muscle cells (SMCs). However, the molecular mechanisms regulating myocardin stability and activity are not well defined. Here we show that the E3 ligase C terminus of Hsc70-interacting protein (CHIP) represses myocardin-dependent SMC gene expression and transcriptional activity. CHIP interacts with and promotes myocardin ubiquitin-mediated degradation by the proteasome in vivo and in vitro. Furthermore, myocardin ubiquitination by CHIP requires its phosphorylation. Importantly, CHIP overexpression reduces the level of myocardin-dependent SMC contractile gene expression and diminishes arterial contractility ex vivo. These findings for the first time, to our knowledge, demonstrate that CHIP-promoted proteolysis of myocardin plays a key role in the physiological control of SMC phenotype and vessel tone, which may have an important implication for pathophysiological conditions such as atherosclerosis, hypertension, and Alzheimer's disease.
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PMID:CHIP represses myocardin-induced smooth muscle cell differentiation via ubiquitin-mediated proteasomal degradation. 1923 36

ATP-binding cassette protein A1 (ABCA1) mediates the transfer of cellular free cholesterol and phospholipids to apolipoprotein A-I (apoA-I), an extracellular acceptor in plasma, to form high-density lipoprotein (HDL). ABCA1 has been suggested to be degraded by proteasome in cholesterol-loaded macrophages, however, the mechanism and regulation of proteasomal degradation of ABCA1 remain unclear. In this study, we analyzed the putative interaction between ABCA1 and COP9 signalosome (CSN), a key molecule in controlling protein ubiquitination and deubiquitination. CSN2 and CSN5, subunits of COP9 CSN complex, were coprecipitated with ABCA1 when coexpressed in HEK293 cells and proteasomal degradation was inhibited by MG132. Overexpression of CSN2 increased endogenous CSN7 and CSN8, and decreased ubiquitinylated forms of ABCA1. These results suggest that CSN is a key molecule which controls the ubiquitinylation and deubiquitinylation of ABCA1, and is thus an important target for developing potential drugs to prevent atherosclerosis.
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PMID:The COP9 signalosome controls ubiquitinylation of ABCA1. 1926 28

Clusterin/apolipoprotein J (CLU) is a secreted glycoprotein associated with many severe physiological disturbances that represent states of increased oxidative stress, such as aging, cancer, atherosclerosis, diabetes, and renal and neurodegenerative diseases. The aim of our work was to examine the effect of proteasome and lysosome inhibition on CLU expression and to determine whether those proteolytic pathways are implicated in CLU gene regulation and protein degradation. To this end we used two different model systems, namely the U-2 OS osteosarcoma cell line and the WI38 primary human embryonic lung fibroblasts. We report that proteasome inhibition promotes both heat-shock factor 1 (HSF-1)-dependent CLU gene expression induction and protein accumulation due to reduced degradation. In contrast, lysosome inhibition results in elevated levels of CLU protein but does not affect the CLU mRNA levels. We also provide direct evidence that both the intracellular precursor, psCLU, and the mature secreted, sCLU, isoforms constitute proteolytic substrates of the proteasome and the lysosome. Overall our findings indicate that CLU overexpression after proteasome inhibition relates to both positive gene transcriptional regulation by HSF-1 and posttranslational protein accumulation due to reduced proteasomal and lysosomal degradation.
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PMID:Transcriptional and posttranslational regulation of clusterin by the two main cellular proteolytic pathways. 1935 83

Rising interest in the mechanism and function of the proteasomes and the ubiquitin system revealed that it is hard to find any aspect of the cellular metabolic network that is not directly or indirectly affected by the degradation system. This includes the cell cycle, the "quality control" of newly synthesized proteins (ERAD), transcription factor regulation, gene expression, cell differentiation, immune response or pathologic processes like cancer, neurodegenerative diseases, lipofuscin formation, diabetes, atherosclerosis, inflammatory processes or cataract formation and in addition to that the aging process itself and the degradation of oxidized proteins, in order to maintain cell homeostasis. But also this seems to be only a small aspect of the general view. The various regulator proteins that are able to change the rate or specificity of proteolysis, fitting it out for highly specialized tasks, or the precise regulation of the half-life of cellular proteins by ubiquitin-mediated degradation shape the proteasome and the ubiquitin-proteasome system into a fascinating and essential part of cellular function in the three kingdoms of bacteria, plants and animals. This review tries to summarize the current knowledge on the proteasome and the ubiquitin-proteasomal system, including the cellular functions of this system.
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PMID:The proteasomal system. 1937 62


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