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)

Smooth muscle cell (SMC) proliferation is suppressed in intact blood vessels but stimulated in atherosclerosis, restenosis after angioplasty, and vein graft disease. The cyclin-dependent kinase inhibitors, including p27(Kip1), play important roles in maintaining SMC quiescence. Levels of p27(Kip1) are dependent on attachment to and the composition of the extracellular matrix (ECM). Here we sought to elucidate mechanisms underlying the ECM-dependent regulation of p27(Kip1) and hence, SMC proliferation. Serum stimulation decreased p27(Kip1) levels in isolated SMC but not in rat aorta. The effect was post-translational and mediated by proteasomal degradation. We studied the S-phase-associated kinase protein-2 (Skp-2), an F-box protein involved in ubiquitination and proteasome-mediated degradation. Skp-2 protein is strongly induced by serum from undetectable levels in isolated SMCs but remains undetectable in aorta; Skp-2 mRNA is also lower in aorta. Overexpression of wild-type Skp-2 in SMCs decreased p27(Kip1) levels, whereas dominant negative F-box deleted mutant (DeltaF-Skp-2) Skp-2 increased p27(Kip1) levels. Furthermore, hyperphosphorylation of retinoblastoma protein and SMC proliferation were also reciprocally affected by wild-type and dominant negative Skp-2. Skp-2 expression was absolutely dependent on cell attachment to the ECM and was inhibited by laminin and type-1 fibrillar collagen but increased by fibronectin. Expression of Skp-2 protein, but not mRNA, was associated with focal adhesion kinase (FAK) activity and inhibited by overexpression of FAK-related non-kinase and a dominant negative FAK(Y397F) mutant. Furthermore, the inhibition of Skp-2 expression by dominant negative FAK was reversed by the proteasome inhibitor MG-132. Taken together, these data demonstrate that the vascular ECM controls SMC proliferation via FAK-dependent regulation of Skp-2 protein stability.
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PMID:Focal adhesion kinase (FAK)-dependent regulation of S-phase kinase-associated protein-2 (Skp-2) stability. A novel mechanism regulating smooth muscle cell proliferation. 1520 31

Hypercholesterolemia (HC) and atherosclerosis often accompany and aggravate renal disease. Proteasome inhibitors (PSI) can decrease proliferation and inflammation, likely by reducing activation of the proinflammatory NF-kappaB. However, chronic proteasome inhibition has never been demonstrated in the HC kidney. Four groups of pigs (n = 7 each) were studied after a 12-wk normal (N) or 2% HC diet alone or supplemented (N+PSI and HC+PSI) with MLN-273 (0.08 mg/kg subcutaneously twice weekly). Renal hemodynamics and function were quantified in vivo using electron-beam computed tomography at baseline and after vasodilator challenge using acetylcholine. Renal tissue was studied ex vivo using immunoblotting, PCR, and immunohistochemistry. Serum cholesterol was similarly elevated in HC and HC+PSI. Basal renal blood flow was similar among the groups, whereas GFR was decreased in both N+PSI and HC+PSI. The blunted renovascular and functional responses to acetylcholine in HC were normalized in HC+PSI (suggesting renal endothelial function improvement), which was accompanied by decreased renal endothelin, NF-kappaB, and augmented endothelial nitric oxide synthase expression. In parallel, HC+PSI animals also showed elevated NAD(P)H oxidase expression and circulating oxidized LDL, suggesting a potential for increased oxidative stress. This study shows that chronic PSI intervention in HC improves renal endothelial functional responses to challenge, possibly by modulating nitric oxide availability and endothelin. Furthermore, PSI may decrease intrarenal inflammation through modulation of the NF-kappaB pathway but may potentially increase oxidative stress, which warrants further investigation. This study may support a role for the ubiquitin/proteasome system in the kidney in HC and early atherosclerosis.
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PMID:Effects of proteasome inhibition on the kidney in experimental hypercholesterolemia. 1571 31

Therapies with antiretroviral protease inhibitors (ARPI) are correlated with a higher risk for dyslipidemia, hypercholesterolemia, and atherosclerosis. The original aim of this study was to establish whether alpha-tocopherol can reduce CD36 scavenger receptor overexpression occurring after treatment of monocytes with the ARPI ritonavir. We show here that treatment of THP-1 monocytes with ritonavir increases total protein and surface expression of CD36; however, only weak changes are observed at the mRNA level, suggesting that CD36 overexpression occurs mainly at the posttranscriptional level. Concentrations of ritonavir that upregulate CD36 expression inhibit proteasome activity in THP-1 cells, indicating a possible regulatory role of the proteasome in CD36 overexpression. Similar to ritonavir, the proteasome inhibitor ALLN increases the CD36 surface expression on THP-1 cells. alpha-Tocopherol efficiently normalizes CD36 protein overexpression after ritonavir treatment and reduces oxLDL uptake. Furthermore, in THP-1 monocytes, alpha-tocopherol reverses the proteasome activity inhibited by ritonavir. This study indicates that an increased CD36 protein expression in THP-1 monocytes induced by ritonavir can be normalized by alpha-tocopherol. CD36 overexpression is caused by inhibition of proteasome activity by ritonavir, which is efficiently restored by alpha-tocopherol.
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PMID:CD36 overexpression in ritonavir-treated THP-1 cells is reversed by alpha-tocopherol. 1578 Jul 63

Prolonged treatments with inhibitors of human immunodeficiency(HIV)-encoded protease (ARPI) have been reported to induce early atherosclerotic events. Our in vitro study indicates that alpha-tocopherol may prevent drug-induced premature atherosclerosis since it interferes with CD36 scavenger receptor over-expression induced by ritonavir in monocytes. The mechanism of CD36 upregulation by ritonavir involves inhibition of the ubiquitin-proteasome system and alpha-tocopherol is able to normalize proteasome activity. These findings suggest that ARPI combined with early alpha-tocopherol supplementation may decrease the drug-induced atherosclerotic risk.
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PMID:HIV protease inhibitors-induced atherosclerosis: prevention by alpha-tocopherol. 1581 62

Dioxins are a class of polyhalogenated aromatic hydrocarbons that induce a wide spectrum of toxic responses in experimental animals. In this study, 2,3,7,8-tetrachlorobenzo-p-dioxin (TCDD) was exposed to two SD rat groups; one group for short-term exposure at a single dose of 1, 10, 20 and 50 mug/kg body weight (group 1) and the other for long-term exposure at daily and-low dose of 0.01, 0.1, 1 and 2.5 microg/kg body weight (group 2) for a month. Two-dimensional electrophoresis (2-DE) was utilized to resolve the protein profile of rat liver exposed to TCDD at different doses. In the analysis of 2-DE of the group 1, two new-expressed spots and seven volume-increased spots were detected and identified by ESI-Q-TOF MS/MS; especially, proteasome subunit beta type 3 was increased in all doses. In addition, in the group 2, six volume-increased spots were screened; particularly, histidine triad nucleotide binding protein was increased in both 0.1 microg/kg dose and 1 microg/kg dose. The identified proteins were confirmed using Western blot. Among the identified proteins, apolipoprotein A-IV may protect lipid peroxidation and atherosclerosis induced by TCDD exposure and the expression level of phosphoglycerate mutase increases due to hyperthyroidism induced by TCDD exposure.
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PMID:Proteomic characterization of rat liver exposed to 2,3,7,8-tetrachlorobenzo-p-dioxin. 1582 8

Proteasomes, multisubunit complexes that consist of a 20S proteasome and a 19S regulatory complex, are essential for several cellular processes. Our interest in the proteasome complex stems from our observations that a novel photoactivable lipopolysaccharide (LPS) probe binds to specific proteasome subunits, and that LPS enhances the chymotrypsin-like activity of the proteasome to degrade synthetic peptides in vitro. Experiments with proteasome inhibitors have shown that expression of many LPS-inducible genes, including TLR2, is inhibited in macrophages. More important, proteasome inhibitors such as lactacystin can prevent LPS-induced shock in mice. This article focuses on the role of the proteasome in the development of inflammatory processes, which may result in septic shock, hemorrhagic shock, atherosclerosis, and neurodegenerative disorders. Taken collectively, the results suggest a potentially important role of the proteasome in inflammation and other macrophage functions.
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PMID:The proteasome: a central regulator of inflammation and macrophage function. 1588 15

Smoking is a significant risk factor for development of atherosclerosis. However, the pathophysiology of smoking-mediated vessel wall damage is not understood. With tools ranging from analytical chemistry to cell biology, we show that cigarette smoke contains metals that catalyze the direct oxidation of cellular proteins by smoke oxidants. Oxidation of cellular proteins causes a loss of microtubule function, culminating in microtubule depolymerization and proteasome-dependent degradation of alpha-tubulin. As a consequence of the microtubule collapse, cytoskeletal structures as well as intermediate filaments break down, leading finally to a contraction of vascular endothelial cells. We observed a smoke extract-induced, calpain-dependent degradation of the intracellular form of platelet-endothelial cell adhesion molecule 1/CD31, as well as a release of P-selectin/CD62P, IL-6, and IL-8 from endothelial cells into the supernatant. Increased levels of soluble CD62P and IL-6 are well known to be associated with smoking in humans. Increased permeability of the vascular endothelium is a crucial event in atherogenesis. This work highlights the compounds and mechanisms by which cigarette smoke induces leakiness of the vascular endothelium.
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PMID:Cigarette smoke metal-catalyzed protein oxidation leads to vascular endothelial cell contraction by depolymerization of microtubules. 1598 33

The ubiquitin-proteasome system is the two sequential labeling and degradation system that accounts for the degradation of 80-90% of all intracellular proteins. Based on the diversity of its substrates, it is integrated in many different biological processes, especially inflammation and cell proliferation. Given the significance of these two processes for primary atherosclerosis and restenosis, the ubiquitin-proteasome system may be an amendable target in cardiovascular therapy. This review provides background information on the ubiquitin-proteasome system, currently available data on its involvement in cardiovascular diseases, and a future perspective on the targeted use proteasome inhibitors, including drug-eluting stents.
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PMID:The ubiquitin-proteasome system--micro target for macro intervention? 1601 9

Complement (C) activation is thought to contribute to the initiation and progression of atherosclerosis. Proliferation of smooth muscle cells plays an important role in atherosclerotic plaque formation. Our aim was to investigate the suitability of the rat aortic smooth muscle cell line A7r5 as an in vitro model to study C-induced events in smooth muscle cells. A7r5 cells abundantly expressed membrane bound C-regulators (CReg) Crry and CD59 as assessed by flow-cytometry, but no DAF or MCP was detected. Using RT-PCR in addition to Crry and CD59, also mRNA for rat DAF but not for MCP was detected. Flow-cytometry of cells removed by EDTA instead of trypsin demonstrated that A7r5 did express cell surface DAF. Upon prolonged culturing under either logarithmic growing conditions or under conditions where cells were kept over-confluent, two different sub cell lines were obtained, one which had lost the expression of CD59, while the other showed increased expression of DAF and Crry. The change in expression of these CReg resulted in a change in C-susceptibility. Incubation of the A7r5 cells with human serum induced membrane attack complex dependent proliferation. Transfection with human CD59 efficiently protected the cells from C-mediated killing and C-induced cell proliferation. Our results show that A7r5 cells can be used as an in vitro model for C-induced events, but care has to be taken to use the cells at an early stage of passaging as they readily change their phenotype.
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PMID:Characterisation of the complement susceptibility of the rat aortic smooth muscle cell line A7r5. 1651 69

Peroxisome proliferator-activated receptor (PPAR) alpha, gamma, and delta belong to the nuclear hormone receptor superfamily of ligand-activated transcription factors. PPARs regulate metabolic, developmental, and differentiation pathways and play important roles in human diseases, such as diabetes, atherosclerosis, cancer, and chronic inflammation. PPARs are the targets of drugs of widespread clinical use and represent promising targets for discovery of new therapeutics. The interaction of PPARs with the ubiquitin-proteasome system (UPS) has been the subject of limited investigation. The UPS plays an important role in regulating the levels and modulating ligand-dependent and-independent activity of nuclear receptors. This review highlights the current knowledge regarding the interactions of the UPS with PPARs and focuses on the differential regulation of the level and activity of the PPAR isotypes by the UPS in response to selective ligands. Understanding the connections between the UPS and PPARs can provide insights in the actions of existing drugs and raise the possibilities for development of more effective PPAR-based therapeutics.
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PMID:Control of peroxisome proliferator-activated receptor fate by the ubiquitinproteasome system. 1711 5


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