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: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cerebral vasculature is an important target tissue for estrogen, as evidenced by significant effects of estrogen on vascular reactivity and protein levels of endothelial nitric oxide synthase and prostacyclin synthase. However, the presence, localization, and regulation of estrogen receptors in the cerebral vasculature have not been investigated. In this study, we identified the presence of estrogen receptor-alpha (ER-alpha) in female rat cerebral blood vessels and localized this receptor to both smooth muscle and endothelial cells by use of immunohistochemistry and confocal microscopy. With immunoblot analysis, multiple forms of ER-alpha were detected at 110, 93, 82, 50, and 45 kDa in addition to a relatively weak band corresponding to the 66-kDa putative unmodified receptor. The 82-kDa band was identified as Ser(118)-phosphorylated ER-alpha, whereas the 50-kDa band lacks the normal NH(2) terminus, suggestive of an ER-alpha splice variant. Lower molecular mass bands persisted after in vivo inhibition of 26S proteasome activity with lactacystin, whereas the 110- and 93-kDa bands increased. All forms of ER-alpha in cerebral vessels were decreased after ovariectomy but significantly increased after chronic estrogen exposure in vivo.
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PMID:Multiple forms of estrogen receptor-alpha in cerebral blood vessels: regulation by estrogen. 1238 60

Nitric oxide originating from the endothelial cells of the vessel wall is essential for the vascular system. It is produced by the enzyme endothelial nitric oxide synthase (eNOS). Cellular eNOS activity is affected by changes in eNOS synthesis. To address whether degradation also contributes to eNOS activity, the effect of proteasome inhibitors on eNOS-mediated NO synthesis was studied in the microvascular endothelial cell line bEnd.3 and in cultured primary aortic endothelial cells. Surprisingly, agonist-induced increases in eNOS activity were reduced to 42 and 50% in the presence of the proteasome inhibiting drugs MG132 and clasto-lactacystin-beta-lactone, respectively (P < 0.01). The decrease in activity occurred within 1 hour of drug treatment and was not accompanied by a change in intracellular levels of either eNOS or its inhibitor caveolin-1. Taken together, these data may indicate that eNOS is regulated by an interacting protein, different from caveolin-1, that inhibits its activity and is rapidly degraded by the proteasome in the presence of eNOS agonists.
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PMID:Involvement of the proteasome in activation of endothelial nitric oxide synthase. 1292 92

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

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, known as statins, effectively prevent cardiovascular events. In addition to their lipid lowering properties, a variety of pleiotropic effects on cardiovascular cells were demonstrated in vitro and in vivo. It has been hypothized that statins deploy a part of their effects by targeting the proteasome. Statin-induced effects remarkably overlap with effects obtained by inhibition of the proteasome in endothelial and vascular smooth muscle cells (e.g., endothelial nitric oxide synthase (eNOS)-upregulation, attenuation of nuclear factor kappa B (NF-kappaB) activation, inhibition of proliferation). We therefore examined, whether statins modulate the proteasomal activity of vascular cells. We studied the effect of simvastatin, atorvastatin, and pravastatin as well as of the proteasome inhibitor clasto-lactacystin on morphology, proliferation, viability, and proteasomal activity in two mammalian endothelial cell lines (CPAE and Ea.hy962), and in primary vascular smooth muscle cells (VSMCs). Both statins and lactacystin induced comparable morphological changes and attenuated proliferation of calf pulmonary artery cell line (CPAE). Whereas the statin-induced effects were reversed by mevalonic acid, however, the lactacystin-induced alterations were not influenced by mevalonic acid. As expected, lactacystin caused a significant loss of proteasomal activity measured in the extract of treated CPAE cells, whereas the extracts of statin-treated CPAEs exhibited unchanged activities. This result was also confirmed in Ea.hy926 cells and in primary rat VSMCs. We show here, that even high doses of statins do not modulate the activities of purified human 20S proteasomes. We conclude that the similar biological effects of statins and proteasome inhibitors in vascular cells are not due to a common inhibitory mechanism of action on the proteasome.
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PMID:Effect of statins on the proteasomal activity in mammalian endothelial and vascular smooth muscle cells. 1599 38

Endothelial Differentiation-related Factor (EDF)-1 is a low molecular weight polypeptide downregulated in endothelial cells exposed to HIV-1-Tat or the phorbol ester TPA. EDF-1 acts in the cytosol as a calmodulin binding protein, and in the nucleus as a transcriptional coactivator. Here, we show that EDF-1 is downregulated in non-proliferating microvascular endothelial cells. Indeed, both quiescence and senescence reduce the levels of EDF-1 and this is due to protein degradation through the proteasome. We also describe a different subcellular localization of EDF-1 which is mainly nuclear in senescent 1G11 cells. Since (i) endothelial nitric oxide (NO) seems to play a role in endothelial proliferation and (ii) NO is an important mediator involved in the control of vascular tone, inflammatory responses and angiogenesis, it is noteworthy that senescence downregulates the expression and the activity of endothelial nitric oxide synthase (eNOS) in microvascular endothelial cells. On the contrary, quiescence does not affect NOS expression and activity. The modulation of EDF-1 in microvascular endothelial cells might offer new insights into the molecular events involved in angiogenesis and in microvascular dysfunctions in the elderly.
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PMID:Differential expression of EDF-1 and endothelial nitric oxide synthase by proliferating, quiescent and senescent microvascular endothelial cells. 1605 6

Epidemiological studies have demonstrated a high association of inorganic arsenic exposure with vascular diseases. Recent research has also linked this vascular damage to impairment of endothelial nitric oxide synthase (eNOS) function by arsenic exposure. However, the role of eNOS in regulating the arsenite-induced vascular dysfunction still remains to be clarified. In our present study, we investigated the effect of arsenite on Akt1 and eNOS and its involvement in cytotoxicity of vascular endothelial cells. Our study demonstrated that arsenite decreased the protein levels of both Akt1 and eNOS accompanied with increased levels of ubiquitination of total cell lysates. We found that inhibition of the ubiquitin-proteasome pathway by MG-132 could partially protect Akt1 and eNOS from degradation by arsenite together with a proportional protection from the arsenite-induced cytoxicity. Moreover, up-regulation of eNOS protein expression significantly attenuated the arsenite-induced cytotoxicity and eNOS activity could be significantly inhibited after incubation with arsenite for 24 h in a cell-free system. Our study indicated that endothelial eNOS activity could be attenuated by arsenite via the ubiquitin-proteasome-mediated degradation of Akt1/eNOS as well as via direct inhibition of eNOS activity. Our study also demonstrated that eNOS actually played a protective role in arsenite-induced cytoxicity. These observations supported the hypothesis that the impairment of eNOS function by arsenite is one of the mechanisms leading to vascular changes and diseases.
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PMID:Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase. 1623 70

Stroke elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. Thrombolysis with tissue plasminogen activator (tPA) promotes adverse vascular events that limit the therapeutic window of stroke to three hours. Proteasome inhibitors reduce vascular thrombotic and inflammatory events, and consequently protect vascular function. The present study evaluated the neuroprotective effect of bortezomib, a potent and selective inhibitor of the proteasome, alone and in combination with delayed thrombolytic therapy on a rat model of embolic focal cerebral ischemia. Treatment with bortezomib reduces adverse cerebrovascular events including secondary thrombosis, inflammatory responses, and blood brain barrier (BBB) disruption, and hence reduces infarct volume and neurological functional deficit when administrated within 4 h after stroke onset. Combination of bortezomib and tPA extends the thrombolytic window for stroke to 6 h, which is associated with the improvement of vascular patency and integrity. Real time RT-PCR of endothelial cells isolated by laser-capture microdissection from brain tissue and Western blot analysis showed that bortezomib upregulates endothelial nitric oxide synthase (eNOS) expression and blocks NF-kappaB activation. These results demonstrate that bortezomib promotes eNOS dependent vascular protection, and reduces NF-kappaB dependent vascular disruption, all of which may contribute to neuroprotection after stroke.
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PMID:Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator. 1654 76

The endothelial nitric oxide synthase (eNOS) is a critical regulator of cardiovascular homeostasis, whose dysregulation leads to different vascular pathologies. Endoglin is a component of the transforming growth factor beta (TGF-beta) receptor complex present in endothelial cells that is involved in angiogenesis, cardiovascular development, and vascular homeostasis. Haploinsufficient expression of endoglin has been shown to downregulate endothelium-derived nitric oxide in endoglin(+/-) (Eng(+/-)) mice and cultured endothelial cells. Here, we find that TGF-beta1 leads to an increased vasodilatation in Eng(+/+) mice that is severely impaired in Eng(+/-) mice, suggesting the involvement of endoglin in the TGF-beta regulated vascular homeostasis. The endoglin-dependent induction of eNOS occurs at the transcriptional level and is mediated by the type I TGF-beta receptor ALK5 and its downstream substrate Smad2. In addition, Smad2-specific signaling is upregulated in endoglin-induced endothelial cells, whereas it is downregulated upon endoglin gene suppression with small interference RNA (siRNA). The endoglin-dependent upregulation of Smad2 was confirmed using eNOS and pARE promoters, whose activities are known to be Smad2 dependent, as well as with the interference of Smad2 with siRNA, Smurf2, or a dominant negative form of Smad2. Furthermore, increased expression of endoglin in endoglin-inducible endothelial cells or in transfectants resulted in increased levels of Smad2 protein without affecting the levels of Smad2 mRNA. The increased levels of Smad2 appear to be due to a decreased ubiquitination and proteasome-dependent degradation leading to stabilization of Smad2. These results suggest that endoglin enhances Smad2 protein levels potentiating TGF-beta signaling, and leading to an increased eNOS expression in endothelial cells.
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PMID:Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. 1705 29

Recent reports have identified the proteasome as the primary degradation pathway for inducible, neuronal and endothelial nitric oxide synthase (NOS). We have demonstrated that hydroxyurea increased nitric oxide (NO) production in endothelial cells through phosphorylation of eNOS as a short-term effect. We find now that NO production in endothelial cells is dose-dependently stimulated by hydroxyurea, as well as both specific and non-specific proteasome inhibitors, as a long term effect. Prolonged treatment of primary human umbilical vein endothelial cells (HUVEC) with hydroxyurea was found to increase eNOS protein levels without an effect on eNOS mRNA levels, suggesting posttranscriptional control. We observed that the inhibitors of proteasomes that we tested also increased eNOS protein levels in HUVEC. In a proteasome assay, we showed that hydroxyurea inhibited protein degradation in a dose-dependent manner, in both purified 20S proteasome and HUVEC lysates. The NO production induced by hydroxyurea in endothelial cells appears to be mediated by long term posttranscriptional augmentation in eNOS levels via inhibition of the proteasome activity.
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PMID:Hydroxyurea increases eNOS protein levels through inhibition of proteasome activity. 1730 93

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.
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PMID:Vascular protective effects of ezetimibe in ApoE-deficient mice. 1860 52


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