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)

The major cellular components of atherosclerotic lesions in several species have been shown to be smooth muscle cells (SMC) and macrophages. Many studies suggest the composition of a lesion varies depending on the stage of lesion development. For example, macrophages are believed to be involved in the initial events of fatty streak formation in many animals. This communication presents the first cellular study of quail atherosclerosis and demonstrates the alteration of cellular structure during the process of the disease in quail fed a cholesterol diet. Monoclonal antibodies to alpha-actin and chicken macrophages effectively identified the presence of SMC and macrophages, respectively, as constituents of the atherosclerotic lesions. Macrophage presence, as well as SMC proliferation, was observed in early lesions. Although the first cell type to be involved in the initial stages of atherogenesis cannot be defined, the results suggest early intervention of macrophages and SMC. Scanning electron microscopic examination of the aortic arch demonstrates the obvious differences in appearance of the endothelial surface of normal and diseased quail. The accumulation of subendothelial foam cells causes the lumen surface to bulge irregularly into the lumen. The results of the present study are important to the evaluation of the key cellular events of atherogenesis.
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PMID:Immunocytochemical and scanning electron microscopic studies of atherosclerosis in Japanese quail. 153 14

The internal mammary artery (IMA) is used widely in bypass grafting for coronary artery disease because of its resistance to atherosclerotic obstruction. Since there are no data on the ultrastructure of IMA or the phenotype of its smooth muscle cells (SMC), we studied the distal parts of left IMA obtained at the time of surgery from 14 coronary bypass patients, aged 43-67 years. Eight IMA were examined by transmission electron microscopy. The distribution of the cytoskeletal proteins actin, vimentin, and desmin in the intima-media of 6 IMA was studied by immunofluorescence microscopy, polyacrylamide gel electrophoresis, and two-dimensional gel electrophoresis. The intimas were very thin, from 3 to 32 microns. The thinnest regions contained no cells. Most intimal cells had the ultrastructural features of SMC; no foam cells were found. The majority of both intimal and medial SMC had a myofilament-rich phenotype. Cells reacting to antibodies of vimentin, desmin and alpha-actin were found in both intima and media. alpha-Actin formed 67% of all actin isoforms in the intima-medial extracts. Our study confirms ultrastructurally the reported scarcity of atherosclerosis in the human IMA and shows that the majority of SMC in the IMA of even severely atherosclerotic coronary bypass patients are both ultrastructurally and biochemically in a differentiated state, which agrees with their resistance to atherosclerosis.
Atherosclerosis 1989 Oct
PMID:Ultrastructural, immunochemical and electrophoretic study of smooth muscle cells in internal mammary arteries of patients undergoing coronary bypass surgery. 268 63

We investigated two monoclonal antibodies (MAbs) which recognize rabbit atherosclerotic tissues. In particular, one antibody, 2P1A2, is specific for rabbit aortic smooth muscle cells (RASMCs). We used RASMCs in primary culture to produce and screen MAbs directed towards the cell surface. The specificity of the described antibodies was tested on a battery of tissue cryosections of different origin (rabbit, rat and human) by immunological staining. 2P1A2 shows an exclusive immunolabeling for SMCs present inside rabbit atherosclerotic plaque. This MAb shows inside the fibrous plaque a staining similar to two other SMC-specific antibodies (anti-desmin and anti-alpha-actin). In an early stage of atherosclerosis, close to the internal elastic lamina, underlying a fibrous plaque, 2P1A2 detects some SMCs; in contrast, anti-desmin and anti-alpha-actin fail to stain such SMCs. This antibody may be therefore considered as directed specifically against SMCs in an activated state. The other antibody which we describe, 1PC1, stains a pericellular antigen expressed by cultured SMCs and shows a specificity for smooth muscle tissues. 1PC1 MAb strongly stains the fibrous plaque of atherosclerotic rabbit aorta and the recognized epitope is present inside the aortic media. These two antibodies may be useful in the recognition of vascular SMCs during the atherosclerotic process.
Atherosclerosis 1988 Nov
PMID:Detection of atherosclerotic plaque with two monoclonal antibodies. 2P1A2 monoclonal antibody is specific for smooth muscle cells in atherosclerotic plaque. 306 71

Vinculin- and caldesmon-immunoreactive forms and actin isoform patterns were studied in samples of normal and atherosclerotic human aorta. After removal of adventitia and endothelium, the remaining tissue was divided into three layers: media, muscular-elastic (adjacent to media) intima, and subendothelial (juxtaluminal) intima. In media of normal aorta, meta-vinculin accounted for 41.0 +/- 0.9% (mean +/- SEM) of total immunoreactive vinculin (meta-vinculin + vinculin); 150-kDa caldesmon accounted for 78.2 +/- 5.1% of immunoreactive caldesmon (150-kDa + 70-kDa); the fractional contents of alpha-smooth muscle actin, beta-nonmuscle, and gamma-isoactins were 49.0 +/- 0.6%, 30.4 +/- 0.6%, and 20.8 +/- 0.8%, respectively. Muscular-elastic intima was very similar to media by these criteria. In subendothelial intima, the fractional content of meta-vinculin and 150-kDa caldesmon was significantly lower (6.9 +/- 1.5% and 32.7 +/- 7.0%, respectively) than in muscular-elastic intima and media, whereas the isoactin pattern was identical to that in adjacent layers, demonstrating the smooth muscle origin of subendothelial intima cells. In atherosclerotic fibrous plaque, the fractional content of alpha-actin was decreased in subendothelial intima, rather than in media and muscular-elastic intima. Additionally, the proportion of subendothelial intima cells [i.e., the cells that express low amounts of smooth muscle phenotype markers (meta-vinculin, 150-kDa caldesmon, and alpha-actin)] in the total intima cell population increased dramatically in atherosclerotic fibrous plaque. The results suggest that changes in the relative content of meta-vinculin and 150-kDa caldesmon as well as alpha-actin in human aortic intima are associated with atherosclerosis although, in subendothelial intima of normal aorta, a certain smooth muscle cell population exists that expresses reduced amounts of "contractile" phenotype markers, even in the absence of the disease.
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PMID:Modulation of human aorta smooth muscle cell phenotype: a study of muscle-specific variants of vinculin, caldesmon, and actin expression. 314 99

In the present study we demonstrate that the quantitative reduction of meta-vinculin expression parallels histological changes during the course of coronary arteriosclerosis. Immunofluorescence stainings of coronary arteries revealed that vinculin distribution resembled that of other smooth muscle-specific cytoskeletal proteins like alpha-actin, caldesmon or myosin light chain kinase in labeling smooth muscle cells brightly. Although close to arteriosclerotic plaques, the cellularity as measured by the density of nuclei was often not significantly altered. Cells of this location expressed markedly reduced amounts of vinculin, suggesting that they are smooth muscle cells of a synthetic phenotype. To determine the fractional meta-vinculin content in arteriosclerotic lesions, we performed densitometric scanning of immunoblots incubated with anti-vinculin monoclonal antibodies reacting with both meta-vinculin (150 kDa) and vinculin (130 kDa). In parallel, each tissue sample was evaluated histologically for the degree of arteriosclerotic alterations according to the morphometric atheroma score of Stratford et al. (n = 13). In type 1 lesions covering slight intimal thickening, meta-vinculin represented 36% (mean, range 35%-39%) of the total vinculin immunoreactivity. In type 2 lesions consisting of fibrous plaques of up to twice the original artery wall thickness, meta-vinculin accounted for 28% (mean, range 22%-35%) of the total vinculin content. Meta-vinculin was substantially reduced in type 3 lesions (mean 13%, range 8%-18%) which are characterized by extensive atheromatous plaques. Thus, the meta-vinculin/vinculin ratio differed significantly between early, intermediate and advanced phases of coronary arteriosclerotic plaque formation.
Atherosclerosis 1994 Nov
PMID:Expression of meta-vinculin in human coronary arteriosclerosis is related to the histological grade of plaque formation. 784 Aug 6

Most of the current concepts on morphogenesis of atherosclerosis attribute the development of atherosclerotic lesions to the combined effects of two main cellular events: 1) activation of macrophages leading to lipoprotein phagocytosis by scavenger cells, and 2) proliferation of smooth muscle cells (SMC). SMC-like cells producing collagenous fibers and extracellular matrix are particularly involved in the formation of the so-called fibrous caps surrounding the core of an atheroma composed of foam cells and fatty debris. The fiber-forming SMC, in general, are said to result from a proliferation of media SMC which once have moved into the intima. This view of origin of the fiber-forming SMC and the alleged proliferation of media SMC is mainly derived from experimental assays exposing the vessel wall to various kinds of physical or chemical injuries. It is the purpose of this paper to demonstrate that the results of those more or less ephemeral experiments differ from findings obtained from a combined histochemical and morphometric analysis of SMC in the aortic media in spontaneous human arteriosclerosis. Instead of any proliferation, a significant atrophy of SMC occurs in the media with advancing age and progress of atherosclerosis. To some extent, this decrease in numerical and volumetric density of SMC is accompanied with intra- and extracellular calcification. It seems likely that the loss of contractile capacity of the media resulting from wasting of SMC, does slow down the stream of the interstitial fluid in the arterial wall. This stagnation must increase the life span of LDL moving through the interstitial space. The chemical alteration ensuing from aging of LDL mediates its binding to the scavenger receptors and uptake by macrophages. So far, muscular atrophy of the media forms an atherogenic factor of its own, leading to final results similar to those as known from conditions of intravascular aging of LDL in hyperlipoproteinaemia. The augmentation of SMC-like cells in the intima is hardly to be derived from the atrophic media, but rather seems to be due to local proliferation of cells which, in the normal state, do occur in small numbers in the subendothelial space. These so-called myointimal or Langhans-cells share with SMC their content of alpha-actin, but they differ by their stellate configuration from the bipolar shape SMC of the media.
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PMID:Proliferation versus atrophy--the ambivalent role of smooth muscle cells in human atherosclerosis. 794 76

Dedifferentiation and proliferation of vascular smooth muscle cells (VSMCs) are important features of atherosclerosis. The molecular mechanisms are largely unclear; however, protein kinase C (PKC) is a key enzyme in the intracellular signaling pathways that mediate this process. We studied the activity and immunoreactivity of PKC-alpha in primary cultures of VSMCs from rat aortas under different conditions of growth and differentiation. PKC-alpha was determined under the following conditions: (1) during the growth phase and after confluence of cultured (passages 1 through 3) VSMCs, (2) before and after induction of differentiation in VSMCs by retinoic acid, and (3) in primary cultures of VSMCs from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats during early passages. PKC activity was measured by in vitro substrate phosphorylation. PKC-alpha immunoreactivity was assessed by Western blot using specific polyclonal antibodies and by immunostaining with confocal microscopy. Cell proliferation was measured by direct count. The cell phenotype was characterized by immunostaining and Western blot for alpha-actin and desmin. PKC-alpha expression and PKC activity during VSMC growth showed a decrease during rapid growth and an increase in confluent cells. This pattern was associated with the respective changes in cell differentiation. Retinoic acid induced an increase in PKC-alpha expression together with a more differentiated phenotype. Subcultured, rapidly growing VSMCs from SHR showed a decreased PKC-alpha expression compared with cells from WKY rats. To establish cause and effect, we next microinjected either PKC-alpha or inactivated material directly into dedifferentiated cells. We found that cells injected with active PKC-alpha expressed increased amounts of actin compared with control cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differentiation of vascular smooth muscle cells and the regulation of protein kinase C-alpha. 800 Dec 76

To learn more about the interaction of allogeneic transplantation and hypercholesterolemia in the formation of arterial lesions, we performed heterotopic cardiac transplantation in rabbits. We analyzed lesions in both the coronary arteries and the proximal ascending aorta 6 weeks after surgery in both transplanted and native hearts of normocholesterolemic rabbits and those with diet-induced hypercholesterolemia (serum cholesterol, 1638 +/- 366 mg/dL, n = 6, 6 weeks after transplantation). All animals received cyclosporin A (5 mg.kg-1.d-1) for immunosuppression. The transplanted aortas of hypercholesterolemic animals had thicker intimal lesions than did the native aortas (intima/media ratio, 0.67 +/- 0.4 versus 0.08 +/- 0.1, P < .05) and contained more T cells (37.4 +/- 12.8 versus 5.7 +/- 6.2 per high-power field, P < .001). In normocholesterolemic animals (n = 5) the coronary arteries had negligible lesions in the native heart and only slight and inconsistent intimal lesions in the transplanted heart. In the hypercholesterolemic animals, more coronary arteries had intimal lesions in the transplanted hearts than in the native hearts (74% versus 43%). Coronary artery lesions in the native hearts consisted mostly of foam cells, while those in transplanted hearts had more abundant smooth muscle cells as determined by alpha-actin staining. Intimal endothelial cells in transplanted aortas expressed increased levels of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 compared with the native vessels subjected to identical levels of cholesterolemia. Medial smooth muscle cells in transplanted aortas contained much higher levels of immunoreactive tumor necrosis factor-alpha than did medial cells of the native aorta in the same hypercholesterolemic animals. The intima of transplanted aortas contained prominent microvessels compared with the native aorta of the hypercholesterolemic rabbits. We conclude that even during treatment with doses of cyclosporine that control acute myocardial rejection, hypercholesterolemia and the allogeneic state act together to augment allograft atherosclerosis, T-cell accumulation, intimal neovascularization, local cytokine expression, and indices of cell activation in arteries.
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PMID:Interaction of the allogeneic state and hypercholesterolemia in arterial lesion formation in experimental cardiac allografts. 817 51

Nonrheumatic aortic stenosis of trileaflet aortic valves has been considered to be a "degenerative" process, but the early lesion of aortic stenosis contains the chronic inflammatory cells, macrophages and T lymphocytes. Because lipoprotein deposition is prominent in atherosclerosis, another chronic inflammatory process, this study examined whether lipoproteins accumulate in aortic valve lesions. Immunohistochemical studies were performed to detect apolipoprotein (apo) B, apo(a), apoE, macrophages, and alpha-actin-expressing cells on 18 trileaflet aortic valves that ranged from normal to stenotic. All three apolipoproteins were detected in early through end-stage lesions of aortic stenosis but not in histologically normal regions. Comparison with oil red O staining suggested that most of the extracellular neutral lipid in these valves was associated with either plasma-derived or locally produced apolipoproteins. Thus, in early through end-stage aortic valve lesions, apolipoproteins accumulate and are associated with the majority of extracellular valve lipid. These results are consistent with the hypothesis that lipoprotein accumulation in the aortic valve contributes to pathogenesis of aortic stenosis.
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PMID:Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of 'degenerative' valvular aortic stenosis. 862 74

Stress or heat shock proteins (hsp) are a family of approximately two dozen proteins with a high degree of amino acid sequence homology between different species, ranging from prokaryotes to humans, and are representative of a generalized response to environmental and metabolic stressors. Our previous studies showed increased expression of human hsp60 on endothelial cells of arterial intima with atherosclerotic lesions, and elevated levels of serum antibodies (Ab) against hsp65/60 in subjects with carotid atherosclerosis. To investigate the possible involvement of anti-hsp65/60 Ab in endothelial injury, specific hsp-Ab were isolated from human high titer sera by affinity chromatography and probed on heat-shock human umbilical vein endothelial cells. Purified human anti-hsp65/60 Ab reacted specifically with mycobacterial hsp65, human hsp60, and a 60-kD protein band of heat-shocked endothelial cells. High levels of hsp60 mRNA expression in endothelial cells were found between 4 and 12 h after 30 min treatment at 42 degrees C. In immunofluorescence tests, positive staining of heat-stressed endothelial cells was observed not only in the cytoplasm but also on the cell surface. Furthermore, only heat-stressed, but not untreated, Cr-labeled endothelial cells were lysed by anti-hsp65/60 Ab in the presence of complement (complement-mediated cytotoxicity) or peripheral blood mononuclear cells (antibody-dependent cellular cytotoxicity). Control Abs, including human anti-hsp65/60 low titer antiserum, human Ig fraction deprived of hsp65/60 Ab, and mAbs to Factor VIII, alpha-actin, hsp70, and CD3 showed no cytotoxic effect. In conclusion, human serum anti-hsp65 antibodies act as autoantibodies reacting with hsp60 on stressed endothelial cells and are able to mediate endothelial cytotoxicity. Thus, a humoral immune reaction to hsp60 may play an important role in the pathogenesis of atherosclerosis.
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PMID:Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. 867 20


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