Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerotic plaques exhibit a series of features that are similar to those of chronic inflammation. Based on the fact that during inflammation several cell types synthesize and secrete a group II phospholipase A2 (PLA2), an immunohistochemical study was undertaken to explore whether this enzyme can be identified in human atherosclerotic lesions. Tissue specimens obtained from 13 patients who had undergone arteriectomy and three specimens with advanced atherosclerotic plaques obtained at autopsy were analyzed and compared to arteries free of atherosclerosis. The results showed that in all areas with atherosclerotic lesions, a staining with monoclonal antibodies raised against group II PLA2 was evident. In normal arteries without thickened intima, this immunostaining was completely negative. With the use of specific monoclonal antibodies against macrophages (anti-KP-1) and smooth muscle cells (anti-alpha-actin), PLA2-positive cells were identified as foam cells mainly derived from macrophages. In addition to these cells, other regions of the thickened intima gave a partially positive reaction with anti-PLA2 antibodies, but could not be stained with either anti-KP-1 or anti-alpha-actin. Some of these regions were localized on edges of calcification and cell necrosis. Other PLA2-positive regions seem to be associated with extracellular matrix structures. In summary, the findings of this study may be regarded as further evidence to support the link between atherosclerosis and chronic inflammatory processes. In view of the fact that the in vitro modification of lipoproteins by PLA2-treatment induces lipid deposition in macrophages, the results of this study suggest that group II PLA2 may actively be involved in the formation of foam cells in vivo.
Atherosclerosis 1995 Dec
PMID:Secretory group II phospholipase A2 in human atherosclerotic plaques. 912 19

Endothelin (ET) is a very potent vasoconstrictor peptide, which was originally reported to be produced by endothelial cells and to act locally in a paracrine fashion to regulate vascular tone. Recent studies have demonstrated that endothelin-1 (ET-1) not only is produced by endothelial cells, but is also present in non-endothelial cells of atherosclerotic lesions. The present study was therefore designed to characterize the cell type and distribution of ET-expressing cells in different areas of human atherosclerotic coronary plaques, obtained by directional atherectomy of 30 patients. In addition, ET-1 messenger RNA (mRNA) distribution was studied in human atherosclerotic plaque tissue by in situ hybridization (ISH). The strongest ET-1-like immunoreactivity (ET-1-IR) was present in all cell-rich areas of 27 plaques. In fibrotic areas of 27 tissue samples, ET-1-IR was found in 44 per cent (12/27). ET expression was most prevalent in foamy macrophages (MPs, HAM 56-positive) and myofibroblasts (MFBs, alpha-actin-positive) in the vicinity of necrotic areas with signs of previous intraplaque haemorrhage. By contrast, ET-1-IR was weak and inconsistently found in MPs (11/27; 40 per cent) and MFBs (12/27; 44 per cent) in fibrous areas. Luminal endothelial cells (Ulex europeus agglutinin reaction-positive, UEA) exhibited strong ET-1-IR, whereas endothelial cells of intraplaque microvessels demonstrated inconsistent staining for ET-1. ISH revealed that ET mRNA is produced locally in intimal MPs showing strong ET-1-IR. These findings demonstrate that ET-1 is produced by human MPs, the principal inflammatory cell type in atherosclerosis, suggesting a role for ET-1 in the chronic inflammation associated with complicated atherosclerosis.
 ...
PMID:Endothelin-1-like immunoreactivity in human atherosclerotic coronary tissue: a detailed analysis of the cellular distribution of endothelin-1. 877 87

Tissue factor, a member of the cytokine-receptor superfamily and high-affinity receptor and cofactor for plasma factor VII/VIIa (ref. 1), is the primary cellular initiator of blood coagulation. It is involved in thrombosis and inflammation associated with sepsis, atherosclerosis and cancer, and can participate in other cellular processes including intracellular signalling, metastasis, tumor-associated angiogenesis, and embryogenesis. Here we report that inactivation of the tissue factor gene (TF) results in abnormal circulation from yolk sac to embryo beyond embryonic day 8.5, leading to embryo wasting and death. Vitelline vessels from null mice were deficient in smooth-muscle alpha-actin-expressing mesenchymal cells, which participate in organization of the vessel wall. This implies that tissue factor has a role in blood vessel development.
 ...
PMID:Role of tissue factor in embryonic blood vessel development. 877 17

The changes occuring in smooth muscle cells during the development of atherosclerosis in rabbits fed 2% cholesterol and the effect of vitamin E treatment were investigated. Ex-vivo smooth muscle cells obtained from the aorta of cholesterol-fed rabbits exhibited a 2-fold increase of protein kinase C expression and activity. The cholesterol induced changes in protein kinase C were equally present in the membrane bound and cytosolic fraction of the enzyme. The amount of a control protein alpha-actin was not affected in smooth muscle cell by the high cholesterol diet treatment, indicating that protein kinase C increase was specific. The increase of protein kinase C expression and activity was not significantly affected by vitamin E treatment although a constant trend was noted. The data are discussed in the light of previous smooth muscle cell in vitro experiments.
Atherosclerosis 1996 Oct 25
PMID:Dietary cholesterol-induced changes of protein kinase C and the effect of vitamin E in rabbit aortic smooth muscle cells. 890 51

In this study we asked whether the well-known atherosclerosis resistance of rats might be reduced with aging. Two groups of young, adult and aged Wistar rats, one of which was kept on a standard, low-cholesterol (CT) diet, and the other one was fed a 2% CT diet for 2 months were enrolled. Potential modifications in the phenotypic profile of aortic smooth muscle (SM) were assessed by SDS-gel electrophoresis, Western blotting and immunofluorescence procedures using a panel of monoclonal antibodies to myosin isoforms, cytoskeletal and extracellular matrix proteins. With development and aging, the expression of 196-kD non-muscle-type myosin heavy-chain isoform (MyHC), the EIIIA fibronectin variant and keratins was downregulated, whereas that of the 204- and 200-kD SM-type MyHC isoforms, SM-type alpha-actin and desmin did not change. The levels of hypercholesterolemia achieved in this model did not substantially modify the distribution of the downregulated markers, except for the subendothelial grouping of immature SM cells in aged rats. Morphometric measurements indicated a slight increase of medial cross-sectional area accompanied by a decrease in total SM cell number, both with aging and with hypercholesterolemia. In no circumstance was the presence of atherosclerotic lesions histologically detectable. Bromo-deoxyuridine (BrdU) incorporation analysis revealed a marked age-dependent decline in DNA synthesis and the formation of binucleated cells in aged aortas. This pattern was not influenced by hypercholesterolemia, except in aged rats where BrdU-positive SM cells are almost doubled. Our data indicate that aging and hypercholesterolemia cannot affect the phenotypic stability of rat SM cells and confirm that the change from a fully differentiated to an immature state is a general prerequisite to allow the development of atherosclerotic lesions in mammalian species.
 ...
PMID:Atherosclerosis resistance in rats correlates with lack of expansion of an immature smooth muscle cell population. 925 93

Secretory nonpancreatic type II phospholipase A2 (snpPLA2) hydrolyzes fatty acids at the sn-2 position in phospholipids releasing free fatty acids (FFAs) and lysophospholipids. These products may act as intracellular second messengers or can be further metabolized into proinflammatory lipid mediators. The presence of snpPLA2 in extracellular fluids and serum during inflammation has suggested a role of the enzyme in this process. However, the presence of snpPLA2 in a variety of normal tissues suggests that snpPLA2 may also have physiological functions. Atherosclerosis appears to have an inflammatory component. Here we report on the snpPLA2 localization in normal and atherosclerotic lesions and on the properties of the isolated enzyme. A strong snpPLA2 immunoreactivity was observed in the arterial media that was colocalized with alpha-actin-positive vascular smooth muscle cells (SMCs) in both normal and atherosclerotic vessels. In aortic atherosclerotic lesions, snpPLA2 was observed colocalized with CD68-positive macrophages and HHF-35-positive SMCs and extracellularly in the lipid core. snpPLA2 was isolated from human normal arteries and from aorta with lesions. The enzyme was isolated by acid extraction of normal arterial tissues followed by immunoaffinity chromatography. The purified snpPLA2 had an expected molecular weight of 14 kD by polyacrylamide gel electrophoresis and appeared as a single band in immunoblotting. The enzymatic activity was followed by measuring release of fatty acids from phospholipid liposomes or LDL as substrates. The enzymatic activity was inhibited with two specific inhibitors for human snpPLA2: (1) monoclonal antibody 187 and (2) LY311727, a synthetic selective inhibitor. The mRNA for snpPLA2 was detected with reverse transcriptase polymerase chain reaction. These results indicate that snpPLA2 is present in human arteries and that it is able to hydrolyze phospholipids in LDL. The results support the hypothesis that snpPLA2 can release proinflammatory lipids at places of LDL deposition in the arterial wall.
 ...
PMID:Localization of nonpancreatic secretory phospholipase A2 in normal and atherosclerotic arteries. Activity of the isolated enzyme on low-density lipoproteins. 908 85

The overgrowth of cells of the vessel wall, especially of the smooth muscle cells (SMCs), contributes to the pathogenesis of coronary atherosclerosis and wound repair after coronary angioplasty. However, the association between cellular proliferation in coronary lesions and clinical pathophysiology remains to be clarified in humans. Thus, we investigated proliferative activity in coronary tissues obtained from patients with coronary ischemia. The proliferative activity in tissues obtained by using directional coronary atherectomy (DCA) from 87 coronary lesions was assessed by immunohistochemical staining for the proliferating cell nuclear antigen (PCNA). The lesions were divided into 34 primary lesions and 53 postangioplasty lesions. The 34 primary tissue samples were obtained from 9 patients with stable angina pectoris (SAP) and 25 patients with acute coronary syndromes (ACS). Collectively, the 53 postangioplasty tissue samples were obtained from 37 patients with SAP and 16 patients with ACS. The PCNA labeling index (LI) was quantified as the mean percentage of PCNA-positive cells in the 3 most positive high-power fields (x 200). The mean LIs were high in the primary ACS samples [8.9 +/- 2.1% (p = 0.01)] and postangioplasty samples [2.3 +/- 0.8% (p = 0.08) in SAP cases and 4.1 +/- 2.4% (p = 0.06) in ACS cases] compared with the primary SAP samples (0.2 +/- 0.2%). Intimal hyperplasia, a random proliferation of SMCs (alpha-actin positive) was marked in the primary ACS samples (76%) as well as in the postangioplasty SAP (92%) and ACS (81%) samples, as compared with the primary SAP samples (33%) (p < 0.01). PCNA expression was mainly evident in the nucleus of the SMCs and CD68-positive macrophages. Many PCNA-positive cells were localized in plaque areas, as follows: intimal hyperplasia, neovascularized lesions, lesions with macrophage clusters, and lesions near areas of disrupted internal elastic lamina. The levels of PCNA expression in coronary lesions were not associated with the subsequent development of restenosis after DCA. Our findings suggest that the excessive proliferation of vascular wall cells, especially SMCs, is involved in the pathogenesis of ACS and in the process of wound repair after angioplasty in humans.
 ...
PMID:Comparison of proliferative activity in coronary plaques from patients with coronary ischemia. Histopathological and immunohistochemical analysis. 911 65

Accumulation of extracellular matrix, fibrosis, is regarded to be one of the major manifestations of atherosclerosis. Collagen type I is the predominant matrix component in human atherosclerotic plaques. In this work we have demonstrated procollagen type I expressing cells (PCI-cells) and studied their localization in grossly normal human aorta and atherosclerotic lesions: initial lesions, fatty streaks, fibrolipid lesions (fibrolipid plaque, fibroatheroma), fibrotic lesions (fibrous plaque). PCI-cells were revealed immunocytochemically using SPI.D8 monoclonal antibody against human procollagen type I. We failed to detect PCI-cells in the areas of grossly normal aorta and media underlying atherosclerotic lesions. Positively stained cells were shown in the areas of initial lesions, fatty streaks, fibrolipid and fibrous plaques. The largest amount of PCI-cells was revealed in fatty streaks. These cells were predominantly localized in the preluminal proteoglycan-rich intimal sublayer. Intimal cells in grossly normal regions formed a common cellular network contacting each other with their processes. The cellular network is found to be partly disintegrated in atherosclerotic lesions, which leads to the appearance of isolated cells. The share of isolated PCI-cells localized outside the intimal cellular network was higher in advanced lesions than in the areas of early atherosclerotic lesions. In initial lesions most of PCI-cells were identified as smooth muscle cells using antibodies to smooth muscle alpha-actin. In fatty streaks PCI-expressing smooth muscle cells were fewer in number. Much fewer cells double-stained with anti-alpha-actin and anti-PCI antibodies were found in fibrolipid and fibrous plaques. The proportion of these double stained cells was higher among total number of PCI-cells involved in the cellular network versus PCI-cells outside the network. The results of the study demonstrated that the most active de novo synthesis of interstitial collagen takes place in the regions of atherosclerotic lesions characterized by lipid deposition, which may lead to the further progression of atherosclerotic lesions.
Atherosclerosis 1997 Apr
PMID:Collagen-synthesizing cells in initial and advanced atherosclerotic lesions of human aorta. 912 57

Thiazolidinediones, insulin-sensitizing agents that lower insulin and lipid levels in insulin-resistant states, block agonist-induced Ca2+ entry into vascular smooth muscle (VSM) cells in vitro and lower blood pressure in animals and humans in vivo. In this study, we investigated the effects of ciglitazone and troglitazone on cell growth and DNA synthesis (as thymidine incorporation), and differentiation in cultured human aorta (haVSM) and human coronary artery (hcaVSM) VSM cells. Mitotically quiescent haVSM cells were stimulated with serum or platelet-derived growth factor (PDGF). Ciglitazone (40 micromol/L) inhibited haVSM cell proliferation by 84 +/- 16% (mean +/- SEM) (P < .05, n = 3), and serum and PDGF stimulated [3H]-thymidine incorporation by 91 +/- 18% (P < .03, n = 3) and 73 +/- 14% (P < .03, n = 4), respectively. Troglitazone (5 micromol/L) inhibited proliferation of haVSM cells by 78 +/- 14% (P < .05, n = 3) and hcaVSM cells by 91 +/- 18% (P < .05, n = 3). Proliferating VSM cells (synthetic phenotype) expressed small amounts of alpha-actin, whereas nonproliferating VSM cells (contractile phenotype) exhibited abundant alpha-actin. Exposure of proliferating haVSM cells to 40 micromol/L ciglitazone induced a marked increase in alpha-actin staining, consistent with transition to the well differentiated, contractile phenotype. To the extent that thiazolidinediones similarly affect growth factor-induced proliferation and differentiation of arterial myocytes in vivo, these agents may be useful in treating atherosclerosis and in preventing restenosis after angioplasty.
 ...
PMID:Effects of thiazolidinediones on growth and differentiation of human aorta and coronary myocytes. 912 11

Smooth muscle cell differentiation and proliferation are increasingly seen to be intimately tied to the etiology of atherosclerosis and hypertension. To determine the role of PKC alpha in the regulation of smooth muscle cell differentiation and proliferation, the rat embryonic smooth muscle cell line A7r5 was transfected with an expression vector containing the full-length PKC alpha cDNA. Neomycin-resistant clones which exhibited increased PKC alpha levels compared to wild-type cells were selected. The A7r5 cells overexpressing PKC alpha had altered morphology and decreased growth rates compared to wild-type cells and cells transfected only with the neomycin resistance gene. Electrophoretic mobility shift assays showed that nuclear extracts from overexpressing clones gave a different pattern of protein-DNA binding to an AP-1 consensus oligonucleotide compared to wild-type cells. In contrast to the growth characteristics of these clones, their levels of cell differentiation marker proteins such as vinculin and desmin were not affected by PKC alpha overexpression. Moreover, the smooth muscle-specific differentiation marker alpha-actin was markedly reduced, while beta-actin levels were found to remain unchanged. Northern blot analysis confirmed that alpha-actin downregulation occurred at the RNA level. Western blot analysis revealed that A7r5 cells have five different PKC isoforms and that these isoform protein levels were not changed by PKC alpha overexpression. These findings suggest that PKC alpha regulates growth and differentiation of A7r5 smooth muscle cells and that these changes might result from altered expression/function of AP-1 transcription factors.
 ...
PMID:Effects of protein kinase C alpha overexpression on A7r5 smooth muscle cell proliferation and differentiation. 934 91


<< Previous 1 2 3 4 5 6 7 Next >>