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 human stem cell factor (SCF), also termed c-Kit ligand (KL), is a hematopoietic growth factor produced by mesenchymal cells that induces proliferation of bone marrow progenitor cells, megakaryocytes, and mast cells via interaction with c-Kit, its cognate receptor. Expression of the c-kit gene was identified in human platelets by the polymerase chain reaction technique. The presence of the c-Kit receptor was demonstrated by the specific binding of 125I-KL/SCF to ADP-stimulated platelets. The identity of the c-Kit protein was confirmed by immunoreactivity with an anti-c-Kit-specific antibody and by its characterization as a phosphotyrosine-containing protein. Under constitutive conditions, c-Kit was found to be tyrosine-phosphorylated and was associated with a 85-kDa phosphoprotein that could be a fragment of phosphatidylinositol 3-kinase. These data indicate the presence of a new platelet surface molecule that could function in platelet activation. We demonstrate that the secondary wave of platelet aggregation and serotonin secretion induced by epinephrine and ADP, but not by the thromboxane analog U46619, was augmented by KL/SCF. The effect of KL/SCF on epinephrine/ADP-induced platelet activation appeared to be mediated in part through the thromboxane pathway. These data suggest that KL/SCF could modulate hemostasis via interaction with platelets, particularly in conditions where mesenchymal cells are exposed to circulating blood elements, such as in wound healing or atherosclerosis.
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PMID:Human kit ligand (stem cell factor) modulates platelet activation in vitro. 752 Apr 41

It has been confirmed that the receptor protein encoded by the c-kit proto-oncogene is expressed by cells of the hematopoietic, gonadal, pigment, and mast cell lineages and that its ligand, stem cell factor (SCF), is mainly expressed in their microenvironment. In a previous study we investigated the expression of the c-kit gene in human aortic endothelial cells (EC). In the present study we investigated the expression of SCF in human aortic EC and smooth muscle cells (SMC). Reverse transcription (RT)-PCR and Northern blot analyses showed that both human arterial EC and SMC expressed mRNA specific for the SCF gene. In addition, tissue-specific expression of the SCF gene was confirmed by in situ hybridization in the EC and the SMC. Western blot analysis and immunocytochemistry showed evidence of production of SCF protein in both the EC and the SMC. These results indicate the existence of mast cell-SMC interaction and of an autocrine loop of c-kit and its ligand on the surface of EC, suggesting that the interaction between c-kit protein and SCF may play an important role in metabolism of arterial wall and in the pathogenesis of atherosclerosis in the arterial intima.
Atherosclerosis 1997 Mar 21
PMID:Expression of stem cell factor in human aortic endothelial and smooth muscle cells. 910 63

Mast cells are multifunctional, tissue-dwelling cells capable of secreting a wide variety of mediators. They develop from bone marrow-derived progenitor cells, primed with stem cell factor (SCF), which mediates its actions by interacting with the SCF receptor or c-kit on the cell surface. Mast cells continue their maturation and differentiation in peripheral tissue, developing into two well described subsets of cells, MCT and MCTC cells, varying in content of tryptase and chymase as well as in immunobiology. Mast cells are activated by numerous stimuli, including antigen (acting via the high affinity IgE receptor, Fc?RI), superoxides, complement proteins, neuropeptides and lipoproteins resulting in activation and degranulation. Following activation, these cells express mediators such as histamine, leukotrienes and prostanoids, as well as proteases, and many cytokines and chemokines, pivotal to the genesis of an inflammatory response. Recent data suggests that mast cells may play an active role in such diverse diseases as atherosclerosis, malignancy, asthma, pulmonary fibrosis and arthritis. Mast cells directly interact with bacteria and appear to play a vital role in host defense against pathogens. Drugs, such as glucocorticoids, cyclosporine and cromolyn have been demonstrated to have inhibitory effects on mast cell degranulation or mediator release.
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PMID:The human mast cell: functions in physiology and disease. 1153 8

Recent evidence indicates that vascular progenitor cells may be the source of smooth muscle cells (SMCs) that accumulate in atherosclerotic lesions, but the origin of these progenitor cells is unknown. To explore the possibility of vascular progenitor cells existing in adults, a variety of tissues from ApoE-deficient mice were extensively examined. Immunohistochemical staining revealed that the adventitia in aortic roots harbored large numbers of cells having stem cell markers, e.g., Sca-1(+) (21%), c-kit(+) (9%), CD34(+) (15%), and Flk1(+) cells (4%), but not SSEA-1(+) embryonic stem cells. Explanted cultures of adventitial tissues using stem cell medium displayed a heterogeneous outgrowth, for example, islands of round-shaped cells surrounded by fibroblast-like cell monolayers. Isolated Sca-1(+) cells were able to differentiate into SMCs in response to PDGF-BB stimulation in vitro. When Sca-1(+) cells carrying the LacZ gene were transferred to the adventitial side of vein grafts in ApoE-deficient mice, beta-gal(+) cells were found in atherosclerotic lesions of the intima, and these cells enhanced the development of the lesions. Thus, a large population of vascular progenitor cells existing in the adventitia can differentiate into SMCs that contribute to atherosclerosis. Our findings indicate that ex vivo expansion of these progenitor cells may have implications for cellular, genetic, and tissue engineering approaches to vascular disease.
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PMID:Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. 1512 12

Progress in the treatment of human in-stent restenosis (ISR) is hampered by an imprecise understanding of the nature of the cells that occlude vascular stents. Recent studies suggest that circulating vascular progenitor cells may mediate vascular repair and lesion formation. Moreover, functional endothelial progenitor cells appear to play a protective role in attenuating vascular lesion formation. Hence, we sought to answer two important questions: 1). Are primitive cells found in ISR lesions? 2). Is the abundance of cultured angiogenic cells (CACs) in patients with ISR different from that in patients with non-ISR lesions or normal controls? Human coronary atherectomy tissue from 13 ISR, 6 postangioplasty restenosis (RS), and 14 primary (PR) atherosclerotic lesions, as well as 15 postmortem coronary artery cross sections from young individuals without atherosclerosis, were studied. All 13 ISR and 4 of 6 RS tissue specimens contained cells that immunolabeled for the primitive cell marker c-kit and smooth muscle alpha-actin, whereas the intima and media of PR lesions and normal arteries were devoid of c-kit-immunopositive cells. The abundance of peripheral blood mononuclear cell-derived CACs was assessed in 10 patients with ISR, 6 patients with angiographically verified patent stents, and 6 individuals with no clinical evidence of coronary artery disease. CACs were less abundant in ISR patients than in non-ISR controls (13.9 +/- 3.1 vs. 22.3 +/- 6.7 cells/high-power field, P < 0.05), and both of these groups had fewer CACs than non-coronary artery disease patients (37.6 +/- 3.8, P < 0.05). These findings suggest a unique pathogenesis for ISR and RS lesions that involves c-kit-immunopositive smooth muscle cells. Moreover, the paucity of CACs in patients with ISR may contribute to the pathogenesis of ISR, perhaps because of attenuated reendothelialization.
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PMID:c-kit-immunopositive vascular progenitor cells populate human coronary in-stent restenosis but not primary atherosclerotic lesions. 1527 95

In the adventitia of large arteries, dendritic cells are located between nerve fibers, some of which contain substance P. The aim of the present study was to examine whether neurokinin 1 receptor (NK-1R) was expressed by dendritic cells in the arterial wall. Parallel sections of aortic and carotid artery segments were immunostained with anti-NK-1R and cell-type-specific antibodies. Dendritic cells in the arterial wall expressed NK-1R, albeit at a low level. Other cells, which intensely expressed NK-1R, were located along the border between the media and adventitia. They did not co-express any dendritic cell markers, including fascin, CD1a, S100, or Lag-antigen, and were negative for CD68, CD3, and mast cell tryptase. These NK-1R(+) cells were laser-capture microdissected and studied by means of electron-microscopic analysis. The microdissected cells were in direct contact with nerve endings, and their ultrastructure was typical of the interstitial cells of Cajal present in the gastrointestinal tract. Further systematic electron-microscopic analysis revealed that the cells displaying the features typical of interstitial cells of Cajal were a basic element of the human arterial wall architectonics. Arterial interstitial cells of Cajal were negative for c-kit but they expressed vasoactive intestinal peptide receptor 1 (VIPR1). Destructive alterations of contacts between arterial interstitial cells of Cajal and nerve endings were observed in arterial segments with atherosclerotic lesions. The functional significance of the arterial interstitial cells of Cajal and their possible involvement in atherosclerosis and other vascular diseases need clarification.
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PMID:Subset of cells immunopositive for neurokinin-1 receptor identified as arterial interstitial cells of Cajal in human large arteries. 1590 5

Recent data from animal models has demonstrated that both endothelial and smooth muscle progenitor cells contribute to the development of atherosclerosis. However, no data exists concerning the presence of progenitor cells in human atherosclerotic vessels. In the present study, a range of normal and atherosclerotic human arteries were collected from patients undergoing coronary artery bypass surgery. Segments of internal mammary artery (normal controls), and segments of proximal ascending aorta with visible fatty streak were analysed. Immunofluorescence was used to detect a panel of progenitor cell markers. A small number of progenitor cells were identified within neointimal lesions and the adventitia with variable expression of CD34, stem cell antigen (Sca-1), c-kit and VEGF receptor 2 (VEGFR2) markers, but no CD133 expression. On average there was a two- to three-fold increase in progenitor cell number in the adventitia of atherosclerotic vessels compared with normal controls, with a significant difference (p<0.05) in the frequency of cells expressing VEGFR2. Thus, we have provided the first evidence that vascular progenitor cells exist within atherosclerotic lesions, and identified an increased number of progenitor cells in the adventitia of human atherosclerotic vessels. These cells might be a source for smooth muscle cells (SMCs), macrophages and endothelial cells (ECs) that form atherosclerotic lesions.
Atherosclerosis 2007 Apr
PMID:Characterisation of progenitor cells in human atherosclerotic vessels. 1678 46

Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kit-positive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1alpha, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.
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PMID:Formation of large coronary arteries by cardiac progenitor cells. 1821 45

The integrity of the endothelial monolayer is fundamental for the homoeostasis of the vascular system. Functional endothelial cells are also required for the growth of new blood vessels during neovascularization. Although multiple growth factors have been shown to regulate angiogenesis and vascular development, little is known about the complex upstream regulation of gene expression and translation. MicroRNAs (miRNAs) are an emerging class of highly conserved, non-coding small RNAs that regulate gene expression on the post-transcriptional level by inhibiting the translation of protein from mRNA or by promoting the degradation of mRNA. More than 500 human miRNAs have been identified so far, and increasing evidence indicates that miRNAs have distinct expression profiles and play crucial roles in various physiological and pathological processes such as cardiogenesis, haematopoietic lineage differentiation, and oncogenesis. Meanwhile, a few specific miRNAs that regulate endothelial cell functions and angiogenesis have been described. Let7-f, miR-27b, and mir-130a were identified as pro-angiogenic miRNAs. In contrast, miR-221 and miR-222 inhibit endothelial cell migration, proliferation, and angiogenesis in vitro by targeting the stem cell factor receptor c-kit and indirectly regulating endothelial nitric oxide synthase expression. Moreover, some miRNAs are involved in tumour angiogenesis such as the miR-17-92 cluster and miR-378. Early studies also indicate the contribution of specific miRNAs (e.g. miR-155, miR-21, and miR-126) to vascular inflammation and diseases. Thus, the identification of miRNAs and their respective targets may offer new therapeutic strategies to treat vascular diseases such as atherosclerosis, to improve neovascularization after ischaemia, or to prevent tumour progression.
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PMID:Role of microRNAs in vascular diseases, inflammation, and angiogenesis. 1861 48

Statins enhance incorporation of bone marrow-derived cells into experimental neointimal lesions. However, the contribution of progenitor cells to progression of spontaneous atherosclerotic plaques, and the possible modulatory role of statins in this process, remain poorly understood. We compared the effects of rosuvastatin (1 and 10mg/kg BW) and pravastatin (10mg/kg) on progenitor cell mobilisation, recruitment into atherosclerotic plaques, and lesion growth. Statins were administered over 8 weeks to apolipoprotein E knockout mice on atherogenic diet. In addition, mice were lethally irradiated, followed by transplantation of bone marrow from LacZ transgenic mice. Rosuvastatin reduced lesion area and intima-to-media ratio at the brachiocephalic artery compared to vehicle, while both parameters were not significantly altered by pravastatin. Rosuvastatin also augmented endothelialisation (P<0.05) and reduced the smooth muscle cells (SMC) content (P=0.042) of lesions. Numbers of c-kit, sca-1 and flk-1, sca-1 double-positive progenitor cells were significantly increased in rosuvastatin compared to control-treated mice, both in the bone marrow and the peripheral blood. Similarly, the number of spleen-derived acLDL, lectin double-positive progenitor cells (P=0.001) and colony-forming units (P=0.0104) was significantly increased in mice treated with rosuvastatin compared to vehicle alone. In the bone marrow, increased Akt and p42/44 MAP kinase phosphorylation and upregulated SDF1alpha mRNA expression were observed. Importantly, rosuvastatin treatment also increased the plasma levels of c-kit ligand (P=0.003), and the number of c-kit-positive cells within atherosclerotic lesions (P=0.041). Our findings suggest that rosuvastatin reduces the size of atherosclerotic plaques, and this effect appears to involve progenitor cell mobilisation and recruitment into vascular lesions.
Atherosclerosis 2009 Jul
PMID:Rosuvastatin reduces atherosclerotic lesions and promotes progenitor cell mobilisation and recruitment in apolipoprotein E knockout mice. 1911 32


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