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)

Previously, we demonstrated that replication in restenotic coronary atherectomy specimens was an infrequent and modest event. In general, this data was interpreted with caution, as immunocytochemistry for the proliferating cell nuclear antigen (PCNA) was used to subjectively assess proliferation and most of the tissue specimens were resected more than 3 months after the initial interventional procedure. The purpose of the present study was to use a more sensitive method of detecting replication, in situ hybridization for histone 3 (H3) mRNA, to determine the replication profile of human directional atherectomy specimens. Restenotic directional coronary atherectomy specimens from lesions that had undergone an interventional procedure within the preceding 3 months were studied. In addition, larger atherectomy specimens from peripheral arterial lesions were assessed to ensure that pockets of replication were not being overlooked in the smaller coronary specimens. We found evidence for replication in tissue resected from 2/17 coronary and 9/12 peripheral artery restenotic lesions. In contrast, 3/11 specimens resected from primary lesions of peripheral arteries also expressed H3 mRNA. We estimated that the maximum percentage of cells that were replicating in restenotic coronary, restenotic peripheral and primary peripheral artery tissue slides to be <0.5, < or =1.2 and <0.01%, respectively. Replication was found in tissue specimens resected both early and late after a previous interventional procedure. For specimens with >15 replicating cells per slide we found high levels of focal replication. Therefore, cell replication, as assessed by the expression of H3 mRNA, was infrequent in restenotic coronary artery specimens, whereas peripheral restenotic lesions had more frequent and higher levels of replication regardless of the interval from the previous interventional procedure. For all specimens the percentage of cells that were replicating was low, however focal areas with relatively high replication indices were presented. Although replication was more abundant in restenotic lesions it does not appear to be a dominant event in the pathophysiology of restenosis.
Atherosclerosis 2000 Sep
PMID:Replication in restenotic atherectomy tissue. 1099 46

Atherosclerosis is the most frequent cause of death in industrialized countries. Lesions are characterized by lipid deposits, focal thickening of the arterial wall with proliferation of smooth muscle cells (SMC), mononuclear infiltrates and neoformed vessels. In this paper, we studied the proliferative characteristics and cytogenetic alterations of SMC. These cells, expressing specific muscular actin, were diploid with an increased proliferative index for PCNA. A high percentage of SMC showed intense expression of p53. There were signs of chromosomal instability, being the most frequent findings chromosome 7 trisomy and chromosome 11 monosomy. Additionally, the gene for FGF-3 showed a marked amplification. These findings strongly suggest that SMC proliferation is active, and is related to the accumulation or mutation of the p53 oncoprotein. It also presents specific chromosomal alterations in close relation with growth factors. According to these findings SMC hyperplasia in the atherosclerosis plaque may be considered as a cellular clonal expansion.
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PMID:[Proliferative activity and chromosomal alterations of smooth muscle cells in atherosclerosis]. 1118 99

Werner syndrome (WS) is an autosomal recessive disease manifested by the premature onset of age-related phenotypes, including diseases such as atherosclerosis and cancer. This mimicry of normal aging with the possible exception of central nervous system manifestations has made it a focus of recent molecular studies on the pathophysiology of aging. In culture, cells obtained from patients with WS are genetically unstable, characterized by an increased frequency of nonclonal translocations and extensive DNA deletions. The WS gene product (WRN) is a DNA helicase belonging to the RecQ family, but is unique within this family in that it also contains an exonuclease activity. In addition to unwinding double-stranded DNA, WRN helicase is able to resolve aberrant DNA structures such as G4 tetraplexes, triplexes and 4-way junctions. Concordant with this structure-specificity, WRN exonuclease preferentially hydrolyzes alternative DNA that contains bubbles, extra-helical loops, 3-way junctions or 4-way junctions. WRN has been shown to bind to and/or functionally interact with other proteins, including replication protein A (RPA), proliferating cell nuclear antigen (PCNA), DNA topoisomerase I, Ku 86/70, DNA polymerase delta and p53. Each of these interacting proteins is involved in DNA transactions including those that resolve alternative DNA structures or repair DNA damage. The biochemical activities of WRN and the functions of WRN associated proteins suggest that in vivo WRN resolves DNA topological or structural aberrations that either occur during DNA metabolic processes such as recombination, replication and repair, or are the outcome of DNA damage.
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PMID:Unwinding the molecular basis of the Werner syndrome. 1134 59

The present study was conducted to evaluate the antiatherogenic effects of dietary gamma-linolenic acid (GLA) (primrose oil) in apolipoprotein E (apoE) genetic knockout mice. Five-wk-old male mice were fed cholesterol-free diets containing 10 g/100 g lipid as corn oil (CO) [control diet, 0 mol/100 mol GLA and (n-3) polyunsaturated fatty acids (PUFA)], primrose oil (PO, 10 mol/100 mol GLA), fish oil-CO mix [FC; 9:1 wt/wt, 0 mol/100 mol GLA and 17 mol/100 mol (n-3) PUFA] or fish oil-PO mix [FP, 1:3 wt/wt, 8 mol/100 mol GLA and 5 mol/100 mol (n-3) PUFA] for 15 wk. Subsequently, diets were supplemented with cholesterol (1.25 g/100 g) and sodium cholate (0.5 g/100 g) and fed for an additional 10 and 16 wk. Plasma cholesterol and triglyceride levels generally did not differ among groups at 20, 30 and 36 wk of age. Mice fed GLA-containing diets (PO and FP) had significantly (P < 0.05) higher liver phospholipid levels of dihomo-gamma-linolenic acid, the elongated product of GLA, relative to CO and FC groups. Consumption of GLA (PO and FP diets) significantly reduced (P < 0.05) aortic vessel wall medial layer thickness at 20 and 30 wk. A parallel GLA-dependent suppression in the number of proliferating (proliferating cell nuclear antigen positive) aortic smooth muscle cells was also observed. Diets containing either GLA or (n-3) PUFA reduced (P < 0.05) atherosclerotic lesion size in 30-wk-old mice. These results indicate that dietary GLA can suppress smooth muscle cell proliferation in vivo and retard the development of diet-induced atherosclerosis in apoE knockout mice.
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PMID:Dietary gamma-linolenic acid suppresses aortic smooth muscle cell proliferation and modifies atherosclerotic lesions in apolipoprotein E knockout mice. 1138 52

There is currently intense interest in the development of gene therapy for cardiovascular disease. The stimulation of therapeutic angiogenesis for ischemic heart disease has been one of the areas of greatest promise. Encouraging results have been obtained with the angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in animal models, leading to clinical trials in ischemic heart disease. VEGF also has therapeutic potential in a second area of cardiovascular gene therapy, the enhancement of arterioprotective endothelial functions to prevent postangioplasty restenosis and bypass graft arteriopathy. The endothelial cell growth and survival functions of VEGF promote endothelial regeneration, whereas VEGF-induced endothelial production of NO and prostacyclin inhibits vascular smooth muscle cell proliferation. Inhibition of neointimal hyperplasia may also be achieved by gene transfer of endothelial NO synthase (eNOS), PGI synthase, or cell cycle regulators (retinoblastoma, cyclin or cyclin-dependent kinase inhibitors, p53, growth arrest homeobox gene, fas ligand) or antisense oligonucleotides to c-myb, c-myc, proliferating cell nuclear antigen, and transcription factors such as nuclear factor kappaB and E2F. An improved understanding of etiologically complex pathologies involving the interplay of genes and the environment, such as atherosclerosis and systemic hypertension, has led to the identification of new targets for gene therapy, with the potential to alleviate inherited genetic defects such as familial hypercholesterolemia. The use of vasodilator gene overexpression and antisense knockdown of vasoconstrictors to reduce blood pressure in animal models of systemic and pulmonary hypertension offers the prospect of gene therapy for human hypertensive disease. The renin-angiotensin system has been the target of choice for antihypertensive strategies because of its wide distribution and additional effects on fibrinolytic and oxidative stress pathways. Gene therapy in cardiovascular disease has an exciting future but remains at an early stage. Further developments in gene transfer vector technology and the identification of additional target genes will be required before its full therapeutic potential can be realized.
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PMID:Gene therapy for cardiovascular disease: a case for cautious optimism. 1171 25

We report here that the traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang (CLM), significantly inhibited the increase in intimal thickening in rat carotid artery injured by balloon endothelial denudation, which mimics many aspects of restenosis after percutaneous coronary intervention (PCI) in humans. CLM, Saiko-ka-Ryukotsu-Borei-to in Japanese, is commonly prescribed for symptoms accompanying hypertension and atherosclerosis in Japanese Kampo medical care. CLM administered orally 1 week before and 1, 4 and 8 weeks after balloon injury inhibited the increase in intimal area, intimal/medial ratio and stenosis ratio. To our knowledge, this is the first report demonstrating inhibitory effects of a traditional Chinese formulation on intimal thickening of carotid artery after balloon injury. It is worth noting that CLM maintained its inhibitory effect up to 8 weeks after balloon injury. The reduction in intimal thickening by CLM could have resulted from inhibition of intimal smooth muscle cell proliferation, which was assessed by immuno-histochemical analysis using monoclonal antibody against proliferating cell nuclear antigen. Therefore, CLM may be a favourable candidate for prevention of restenosis after PCI. Moreover CLM may have a therapeutic value in the prevention of atherosclerosis, because restenosis after PCI is considered to be an accelerated atherosclerosis.
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PMID:Preventive effects of a traditional Chinese formulation, Chaihu-jia-Longgu-Muli-tang, on intimal thickening of carotid artery injured by balloon endothelial denudation in rats. 1199 36

Excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation are critical steps in the pathogenesis of atherosclerosis and restenosis after percutaneous transluminal angioplasty. In this study, we investigated the hypothesis that the activator protein-1 (AP-1) plays an important role in neointimal formation after vascular injury. A circular dumbbell AP-1 decoy oligodeoxynucleotide (CDODN) was developed as a novel therapeutic strategy for restenosis after angioplasty. This CDODN was more stable than the conventional phosphorothioate linear decoy ODN (PSODN) and maintained structural integrity on exposure to exonuclease III or serum. Transfection with AP-1 decoy ODNs strongly inhibited VSMC proliferation and migration, as well as glucose- and serum-induced expression of PCNA and cyclin A genes. Administration of AP-1 decoy ODNs in vivo using the hemagglutinating virus of Japan (HVJ)-liposome method virtually abolished neointimal formation after balloon injury to the rat carotid artery. Compared with PSODN, CDODN was more effective in inhibiting the proliferation of VSMCs in vitro and neointimal formation in vivo. Our results collectively indicate that AP-1 activation is crucial for the mediation of VSMC proliferation in response to vascular injury. Moreover, the use of stable CDODN specific for AP-1 activity in combination with the highly effective HVJ-liposome method provides a novel potential therapeutic strategy for the prevention of restenosis after angioplasty in humans.
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PMID:Inhibitory effects of novel AP-1 decoy oligodeoxynucleotides on vascular smooth muscle cell proliferation in vitro and neointimal formation in vivo. 1208 58

Hyperlipidemia is thought to accelerate the progression of renal diseases, but the mechanisms by which hyperlipidemia exerts its deleterious effect is still poorly understood. The aim of this study was to describe the renal pathology in a hyperlipidemic mouse strain, the apolipoprotein E-deficient mice (apoE-/-). Renal specimens from a total of 34 mice were studied, including 19 apoE-/- females at the age of 36 weeks, 9 apoE-/- females at the age of 24 weeks, and 6 wild-type females (C57BL/6) as controls. Kidneys were evaluated by histologic examination, immunohistochemistry, and electron microscopy. Immunohistochemistry was used to detect MAC-2-expressing monocyte/macrophages, and the proliferation marker PCNA. Glomerular cell number, glomerular matrix area, and glomerular area were quantified by morphometry. Glomerular lesions in apoE-/- mice were characterized by macrophage accumulation, commonly with foam cell appearance, deposition of extracellular matrix, glomerular hyperplasia, and at times prominent mesangiolysis associated with capillary microaneurysms. Some cases demonstrated lipid deposits filling glomerular capillaries. Arterioles of the vascular pole demonstrated a "foamy" degeneration of smooth muscle cells. These lesions related to hyperlipidemia in this well-established mouse strain have not been previously described. Because this mouse strain is among the most widely studied for interventions aimed at altering hyperlipidemia and the progression of atherosclerosis, we believe that our observations may be of major importance for the accurate interpretation of interventional studies in this strain and offer a new opportunity to study mechanisms of hyperlipidemic renal injury.
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PMID:Renal injury in apolipoprotein E-deficient mice. 1217 38

Oral administration of Saiko-ka-Ryukotsu-Borei-To (SRB), a traditional Chinese formulation, dose dependently inhibited intimal thickening in carotid artery injured by balloon endothelial denudation in cholesterol-fed rats. SRB also inhibited vascular smooth muscle cell (VSMC) proliferation, which is assessed by counting the VSMCs immunoreactive with antiproliferating cell nuclear antigen (PCNA) antibody in the intimal area. VSMC proliferation is considered to play a central role in the development of intimal thickening. SRB slightly, but not significantly, reduced serum total cholesterol and low-density lipoprotein cholesterol. These results indicate that the suppressive effect of SRB on intimal thickening may result from its inhibitory effect against VSMC proliferation, but does not depend on lowering of lipid levels. The balloon injury model used in this study has similar pathological processes to restenosis after percutaneous coronary intervention (PCI). Therefore the present results may provide a new therapeutic strategy using SRB to reduce restenosis after PCI in the treatment of patients with ischemic coronary artery disease. Furthermore, since it is considered that artery restenosis after balloon injury in PCI is "accelerated atherosclerosis, " SRB may have beneficial effects in atherosclerosis that develops over a long clinical course in hyperlipidemia, diabetes, etc.
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PMID:Saiko-ka-Ryukotsu-Borei-To inhibits intimal thickening in carotid artery after balloon endothelial denudation in cholesterol-fed rats. 1252 Jan 73

Oxidized low-density lipoprotein (oxLDL) may be involved in atherosclerosis by stimulating proliferation of cells in the vessel wall. The purpose of this study was to identify the mechanism by which oxLDL induces proliferation. Quiescent human fibroblasts and rabbit smooth muscle cells were treated with 0, 10, or 50 microg/ml oxLDL for 24-48 h. This resulted in significant increases in total cell counts at both concentrations of oxLDL, at both time points, for both types of cells. Western blot analysis revealed that oxLDL-stimulated cell proliferation was associated with significant increases in the expression of proteins that regulate entry into and progression through the cell cycle [cell division cycle 2, cyclin-dependent kinase (cdk) 2, cdk 4, cyclin B1, cyclin D1, and PCNA]. Surprisingly, the expression of cell cycle inhibitors (p21 and p27) was stimulated by oxLDL as well, but this was to a lesser extent than the effects on cell cycle-activating proteins. OxLDL also induced nuclear localization of all cell cycle proteins examined. The similar effects of oxLDL on the translocation and expression of both cell cycle-activating and -inhibiting proteins may explain the controlled proliferative phenomenon observed in atherosclerosis as opposed to the more rapid proliferative event characteristic of cancer.
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PMID:OxLDL stimulates cell proliferation through a general induction of cell cycle proteins. 1252 57


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