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)

Elevated levels of oxidized proteins are reported in diseased tissue from age-related pathologies such as atherosclerosis, neurodegenerative disorders, and cataract. Unlike the precise mechanisms that exist for the repair of nucleic acids, lipids, and carbohydrates, the primary pathway for the repair of oxidized proteins is complete catabolism to their constitutive amino acids. This process can be inefficient as is evidenced by their accumulation. It is generally considered that damaged proteins are degraded by the proteasome; however, this is only true for mildly oxidized proteins, because substrates must be unfolded to enter the narrow catalytic core. Rather, evidence suggests that moderately or heavily oxidized proteins are endocytosed and enter the endosomal/lysosomal system, indicating co-operation between the proteasomes and the lysosomes. Heavily modified substrates are incompletely degraded and accumulate within the lysosomal compartments resulting in the formation of lipofuscin-like, autofluorescent aggregates. Accumulation eventually results in impaired turnover of large organelles such as proteasomes and mitochondria, lysosomal destablization, leakage of proteases into the cytosol and apoptosis. In this review, we summarize reports published since our last assessments of the field of oxidized protein degradation including a role for modified proteins in the induction of apoptosis.
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PMID:Oxidized proteins: mechanisms of removal and consequences of accumulation. 1939 Nov 65

Increased levels of oxidized low-density lipoproteins (oxLDL) contribute to the increased risk for atherosclerosis, which persists even after adjusting for traditional risk factors, among patients with ESRD. Regulatory T cells (CD4+/CD25+ Tregs), which down-regulate T cell responses to foreign and self-antigens, are protective in murine atherogenesis, but whether similar immunoregulation occurs in humans with ESRD is unknown. Because cellular defense systems against oxLDL involve proteolytic degradation, the authors investigated the role of oxLDL on proteasome activity of CD4+/CD25+ Tregs in patients with ESRD. CD4+/CD25+ Tregs isolated from uremic patients' peripheral blood, especially that of chronically hemodialyzed patients, failed to suppress cell proliferation, exhibited cell-cycle arrest, and entered apoptosis by altering proteasome activity. Treating CD4+/CD25+ Tregs with oxLDL or uremic serum ex vivo decreased the number and suppressive capacity of CD4+/CD25+ Tregs. In vitro, oxLDL promoted the accumulation of p27Kip1, the cyclin-dependent kinase inhibitor responsible for G1 cell cycle arrest, and increased apoptosis in a time- and concentration-dependent manner. In summary, proteasome inhibition by oxLDL leads to cell cycle arrest and apoptosis, dramatically affecting the number and suppressive capacity of CD4+/CD25+ Tregs in chronically hemodialyzed patients. This response may contribute to the immune dysfunction, microinflammation, and atherogenesis observed in patients with ESRD.
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PMID:Oxidized LDL modulates apoptosis of regulatory T cells in patients with ESRD. 2445 34

The ubiquitin-proteasome system is involved in the development and progression of atherosclerosis. The aim of this study was to investigate whether plaque composition is affected by proteasome function. In vitro, the potent and selective proteasome inhibitor bortezomib induced apoptosis in both cultured smooth muscle cells (SMCs) and activated macrophages. This effect was associated with increased expression of C/EBP homologous protein and cleavage of caspase-12, indicative of endoplasmic reticulum stress. The sensitivity to the proapoptotic effects of proteasome inhibition correlated with the protein synthesis rate. Proteasome inhibition in explanted atherosclerotic plaques of ApoE-deficient mice resulted in a significant decrease in SMCs and macrophages, indicating that both cell types in the atherosclerotic plaque were susceptible to the proapoptotic effects of proteasome inhibition. In vivo proteasome inhibition in ApoE-deficient mice did not affect plaque size or composition of early atherosclerotic plaques, but resulted in a significant decrease in collagen content as well as a significant enlargement of the necrotic core in advanced atherosclerotic plaques. In conclusion, our results indicate that an impaired proteasome function promotes features of a more rupture-prone plaque phenotype.
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PMID:Proteasome inhibitor bortezomib promotes a rupture-prone plaque phenotype in ApoE-deficient mice. 1969 27

Protein metabolism is a central element of every living cell. The ubiquitin-proteasome system (UPS) is an integral part of the protein metabolism machinery mediating post-transcriptional processing and degradation of the majority of intracellular proteins. Over the past few years, remarkable progress has been made in our understanding of the role of the UPS in vascular biology and pathobiology, particularly atherosclerosis. This review reflects on the recent developments from the effects on endothelial cells and the initial stage of atherosclerosis to the effects on vascular smooth muscle and the progression stage of atherosclerosis and finally to the effects on cell viability and the complication stage of atherosclerosis. It will conclude with the integration of the available information in a synoptic view of the involvement of the UPS in atherosclerosis.
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PMID:On to the road to degradation: atherosclerosis and the proteasome. 1981 65

We studied the changes in proteasomal proteolisis during modelling of rabbit cholesterol-induced atherosclerosis. It was determined that in aorta the TL activity of proteasome increased 2.4-fold (P < 0.05), CTL activity increased by 43%, and PGPG--by 10%. In heart tissue it was observed the increase of CTL proteasome activity by 14%. The application of "Korvitin" (water-soluble form of quercetine) followed by considerable decrease of proteasomal activity both in tissues (aorta and heart) and leucocytes. The intensity ofatherosclerotic changes in aorta was significantly smaller. Obtained data suggest that "Korvitin" reveales angioprotective properties mediated by it effect on proteasomal proteolisis.
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PMID:[Antiatherogenic characteristics of korvitin: effect on proteasome activity of the aorta, heart, and blood cells]. 1982 30

Inflammation plays a central role in the pathogenesis of atherosclerosis. This study investigated whether the proteasome inhibitor has the same preventive effect on the formation of accelerated atherosclerosis in rabbits with uremia compared with a NF-kappaB inhibitor. New Zealand white rabbits were subjected to five-sixths nephrectomy (chronic renal failure [CRF]) or to a sham operation. Rats in each group were randomly assigned into three subgroups (n = 24 in each group) and treated with repeated intramuscular injections of proteasome inhibitor MG132 or NF-kappaB inhibitor PDTC for a specified period. Compared with sham rabbits, CRF rabbits displayed typical atherosclerotic changes (endothelial cell damage, intimal thickens, and appearance of foam cells). CRF rabbits had significantly higher levels of proteasome activity, NF-kappaB mRNA, protein, and DNA binding activity as well as tumor necrosis factor-a and proliferative cell nuclear antigen protein expression in aortic wall cells. CRF rabbits also showed lower levels of IkappaBalpha. Compared with CRF rabbits, CRF rabbits treatment with proteasome inhibitor MG132 showed restoration of IkappaBalpha mRNA and protein expression and decreased NF-kappaB DNA binding activity and tumor necrosis factor-a expression. Treatment with either proteasome inhibitor MG132 or NF-kappaB inhibitor PDTC could reverse these pathologic changes in the aortic wall cells of CRF rabbits. A comparison between the inhibitory effects of the two treatments revealed no statistical difference. These results suggest that ubiquitin-proteasome activation play a pivotal role in the pathogenesis of uremia-accelerated atherosclerosis. The ubiquitin-proteasome signaling pathway in aortic cells may therefore be an important target for preventing uremia-accelerated atherosclerosis.
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PMID:Preventive effect of a proteasome inhibitor on the formation of accelerated atherosclerosis in rabbits with uremia. 1993 80

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by the dysfunction of T cells, B cells, and dendritic cells and by the production of antinuclear autoantibodies. This editorial provides a synopsis of newly discovered genetic factors and signaling pathways in lupus pathogenesis that are documented in 11 state-of-the-art reviews and original articles. Mitochondrial hyperpolarization underlies mitochondrial dysfunction, depletion of ATP, oxidative stress, abnormal activation, and death signal processing in lupus T cells. The mammalian target of rapamycin, which is a sensor of the mitochondrial transmembrane potential, has been successfully targeted for treatment of SLE with rapamycin or sirolimus in both patients and animal models. Inhibition of oxidative stress, nitric oxide production, expression of endogenous retroviral and repetitive elements such as HRES-1, the long interspersed nuclear elements 1, Trex1, interferon alpha (IFN-alpha), toll-like receptors 7 and 9 (TLR-7/9), high-mobility group B1 protein, extracellular signal-regulated kinase, DNA methyl transferase 1, histone deacetylase, spleen tyrosine kinase, proteasome function, lysosome function, endosome recycling, actin cytoskeleton formation, the nuclear factor kappa B pathway, and activation of cytotoxic T cells showed efficacy in animal models of lupus. Although B cell depletion and blockade of anti-DNA antibodies and T-B cell interaction have shown success in animal models, human studies are currently ongoing to establish the value of several target molecules for treatment of patients with lupus. Ongoing oxidative stress and inflammation lead to accelerated atherosclerosis that emerged as a significant cause of mortality in SLE.
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PMID:Pathogenic mechanisms in systemic lupus erythematosus. 2001 60

The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia/reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible because of their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative "specific" mechanisms. The cytosolic receptors p62, NBR, and histone deacetylase 6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of "selective autophagy." Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease.
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PMID:Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. 2016 43

People with diabetes experience chronic hyperglycemia and are at a high risk of developing atherosclerosis and microvascular disease. Reactions of glucose, or aldehydes derived from glucose (e.g. methylglyoxal, glyoxal, or glycolaldehyde), with proteins result in glycation that ultimately yield advanced glycation end products (AGE). AGE are present at elevated levels in plasma and atherosclerotic lesions from people with diabetes, and previous in vitro studies have postulated that the presence of these materials is deleterious to cell function. This accumulation of AGE and glycated proteins within cells may arise from either increased formation and/or ineffective removal by cellular proteolytic systems, such as the proteasomes, the major multi-enzyme complex that removes proteins within cells. In this study it is shown that whilst high glucose concentrations fail to modify proteasome enzyme activities in J774A.1 macrophage-like cell extracts, reactive aldehydes enhanced proteasomal enzyme activities. In contrast BSA, pre-treated with high glucose for 8 weeks, inhibited both the chymotrypsin-like and caspase-like activities. BSA glycated using methylglyoxal or glycolaldehyde, also inhibited proteasomal activity though to differing extents. This suppression of proteasome activity by glycated proteins may result in further intracellular accumulation of glycated proteins with subsequent deleterious effects on cellular function.
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PMID:Deleterious effects of reactive aldehydes and glycated proteins on macrophage proteasomal function: possible links between diabetes and atherosclerosis. 2017 4

Garlic is viewed as an effective health food against atherosclerosis. In this study, we examined whether diallyl disulfide (DADS) and diallyl trisulfide (DATS) protect endothelial nitric oxide synthase (eNOS) activation against oxidized LDL (ox-LDL) insult and through what mechanism. We found that DADS and DATS reversed the suppression of eNOS Ser1177 phosphorylation by ox-LDL, and wortmannin abolished the reversal by DADS and DATS. Similarly, the inhibition of cellular cGMP and nitric oxide production by ox-LDL was reversed by DADS and DATS (p<0.05). This increase in nitric oxide bioavailability by the allyl sulfides was attenuated by wortmannin. Immunoprecipitation assay revealed that DADS and DATS preserved the interaction of eNOS with caveolin-1 in the membrane. In addition, DADS and DATS suppressed the reduction of the cellular eNOS protein content by ox-LDL. When cycloheximide was added to block protein synthesis, DADS and DATS suppressed eNOS protein degradation similarly to that noted by MG132. Ox-LDL increased chymotrypsin-like proteasome activity, and this increase was inhibited by the allyl sulfides and MG132 (p<0.05). These results suggest that DADS and DATS protect eNOS activity against ox-LDL insult. This protection can be attributed partly to their mediation of phosphatidylinositol 3-kinase/protein kinase B signaling and prevention of eNOS degradation.
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PMID:Diallyl disulfide and diallyl trisulfide protect endothelial nitric oxide synthase against damage by oxidized low-density lipoprotein. 2022 25


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