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)

Restenosis after coronary angioplasty is due to a proliferation of smooth muscle cells growing in the vascular lumen, beneath the residual fragments of the atherosclerotic plaque, as seen in necropsy studies and examination of the specimens removed by atherectomy. At the histological analysis thrombi or their fibrocellular organization are not usually detectable. Smooth muscle cell proliferation leading to restenosis is very similar to the one observed in the experimental models of response-to-injury, so that these models are used to investigate into the pathogenetic mechanisms of restenosis. The main stimulus to the loss of the contractile phenotype and to the start of the smooth muscle cell proliferation is represented by the growth factors delivered by platelets adhered to the disendothelialized wall and by the smooth muscle cells themselves, stretched during the dilatation. Other stimuli can be growth factors delivered by monocytes and fibroblasts, by thrombin, endothelin, angiotensin and interleukin 1. The elastic recoil of the vessel wall, the plaque debris and the regional wall shear stress can also contribute to restenosis. The restenosis tissue is different from the atheromatous plaque in that it is almost only constituted by smooth muscle cells and intercellular matrix, while atheroma is much more complex due to the presence of various kinds of cells, of necrotic debris and lipid substances. The smooth muscle cells proliferation also contributes to the pathogenesis of atherosclerosis, but the stimuli starting this process have not been clarified yet; moreover this process is much slower than restenosis, interacting with several factors. Encouraging results have been achieved in the prevention of restenosis after angioplasty in experimental models, but not in man. In order to reduce the incidence of restenosis one should improve the results of angioplasty, even by the use of atherectomy and intracoronary stents. Among pharmacologic approaches anticoagulants, heparin, antiplatelet agents, calcium-channel blockers, corticosteroids all proved ineffective. Studies are in progress evaluating the effect of inhibitors of platelet-derived growth factor (PDGF), antitumor agents and radiation therapy, hirudin, angiotensin-converting enzyme inhibitors and HMG-CoA reductase inhibitors.
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PMID:[Restenosis after coronary angioplasty: its pathogenesis and prevention]. 184 86

Tyrphostins are low-molecular-weight synthetic inhibitors of protein tyrosine kinase, which block cell proliferation. Since platelet-derived growth factor (PDGF) is thought to figure prominently in disorders of vascular smooth muscle cells (VSMC), such as atherosclerosis, hypertension, and restenosis, we examined whether tyrphostins would inhibit PDGF-induced mitogenesis in VSMC. In this communication, we demonstrate that tyrphostins with the benzenemalononitrile nucleus inhibited PDGF-dependent growth of VSMC as well as PDGF-dependent DNA synthesis in these cells, with the concentrations for 50% inhibition ranging from 0.04 to 9 microM. Up to 30-fold higher tyrphostin concentrations were required to inhibit serum-stimulated DNA synthesis of VSMC. The effect of the tyrphostins is reversible, since on their removal a normal proliferative response to PDGF was resumed. Tyrphostins also inhibited PDGF-receptor autophosphorylation and PDGF-induced phosphorylation of intracellular substrates, including the phosphorylation of phospholipase C-gamma, with a potency ratio similar to their antimitogenic activity. The expression of c-fos mRNA, a mitogenic nuclear signal, was also reduced in PDGF-stimulated VSMC treated with tyrphostins at concentrations which inhibit PDGF-induced mitogenesis. It is concluded that tyrphostins are potent reversible inhibitors of PDGF-induced mitogenesis which act by inhibiting the tyrosine kinase activity of the PDGF receptor and the subsequent signaling cascade. Tyrphostins may be useful in the study and treatment of VSMC proliferation disorders.
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PMID:Tyrphostins inhibit PDGF-induced DNA synthesis and associated early events in smooth muscle cells. 185 Jan 95

The effects of prolactin (PRL) on A10 (aortic smooth muscle) cell proliferation were examined by measuring both [3H]thymidine incorporation and increases in cell number. PRL induced a significant proliferative response from 10(-11) to 10(-7) M, with optimal activity at 10(-10) M. PRL also enhanced platelet-derived growth factor (PDGF)-induced proliferation. The possibility that PRL induces proliferation through a protein kinase C (PKC)-mediated mechanism was also examined. PRL caused activation of PKC from 10(-12) to 10(-8) M. Antiserum to PRL, a monoclonal antibody directed against the PRL receptor and the immunosuppressive agent cyclosporine A, were able to inhibit PRL-induced proliferation and activation of PKC. The PKC inhibitors, staurosporine, sphingosine, and 1-(-5-iso-quinoline-sulfonyl)-2-methylpiperazine (H-7) also antagonized both proliferation and PKC activation. These data strongly suggest that PRL-induced A10 cell proliferation is mediated through the PKC pathway and that this may play a role in vascular smooth muscle cell hyperplasia, characteristic of the pathogenesis of cardiovascular diseases such as hypertension and atherosclerosis.
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PMID:Prolactin induces proliferation of vascular smooth muscle cells through a protein kinase C-dependent mechanism. 186 Aug 93

The major components of atherosclerotic plaque, ultimately responsible for clinical effects, are deposited lipids--mostly cholesteryl esters and cholesterol, derived largely from the lower-density lipoproteins of the blood--and proliferated, modified arterial smooth muscle cells with their synthesized connective tissue products. Advanced plaques vary widely in the proportion of the two components, but evidence indicates that lipid deposition--especially of lipoprotein elements--often occurs in the lesion-prone intimal areas of the artery prior to the buildup of smooth muscle cells. The 1980s were remarkably productive for investigators who study the pathogenesis of atherosclerosis. We now know of the many forms of lower-density lipoproteins, i.e., low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL), some of which are more likely to be associated with accelerated atherosclerosis and some of which are more likely to be influenced by diet. Among these forms of LDL and VLDL are LDL-1, beta-VLDL, and Lp(a). Work has been reported implicating various alterations of endothelial function in the permeability of the arterial endothelial barrier in the transport of these low-density, cholesterol-rich macromolecules. Of possibly greater interest is the developing evidence that such proliferation-stimulating molecules as platelet-derived growth factor (PDGF) can be produced by a number of cells likely to be involved in the progression of atherosclerotic plaque. In addition to platelets, these include activated monocytes and monocyte-derived macrophages, injured endothelial cells, and smooth muscle cells, which can undergo an autocrine conversion to PDGF synthesis--possibly stimulated by LDL from hyperlipidemic serum. Leukotrienes and other endothelium-associated regulatory molecules may also take part in the paracrine and autocrine mechanisms of stimulating smooth-muscle-cell proliferation. Additional recent developments that have led to a better understanding of atherosclerotic pathogenesis have occurred. The first is evidence of the involvement of oxidized LDL and its apolipoprotein B in atherogenesis. Research indicates that antioxidants have a suppressive effect on atherogenesis when oxidized LDL has been involved in lesion development. The data linking the development of autoimmune reactions to these oxidatively altered lipoproteins are also impressive. Further, there is increasing evidence that atherogenesis in nonhuman primates and in people in whom chronic sustained circulating immune complexes are involved is likely to be accelerated, even when few or no classic risk factors are present. These lesions appear to represent a distinct microarchitectural form of concentric and transmural atherosclerosis that is better classified as "atheroarteritis."
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PMID:Update on the pathogenesis of atherosclerosis. 186 33

We have investigated the growth promoting activities of two potent vasoactive substances, serotonin and angiotensin II (AII), on cultured porcine aortic smooth muscle cells (ASMC), using a defined serum-free medium. Serotonin (30 nM to 30 microM) stimulated ASMC DNA synthesis both alone and in combination with platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). Serotonin-induced DNA synthesis was significantly inhibited by ketanserin (5-hydroxytryptamine-2 (5HT-2) receptor antagonist). AII (3-10 nM) failed to stimulate ASMC DNA synthesis directly, either alone or in combination with PDGF or EGF. Since both serotonin and AII were found to activate phosphatidylinositol turnover and are reported to mobilise intracellular calcium, it is apparent that these events alone are insufficient to stimulate ASMC mitogenesis.
Atherosclerosis 1991 Jun
PMID:Comparison of the mitogenic activity of angiotensin II and serotonin on porcine arterial smooth muscle cells. 189 86

Transforming growth factor (TGF)-beta 1 may have different effects on cell proliferation depending on many conditions. This paper clarifies the effects of various conditions on the effect of TGF-beta 1 on proliferation of cultured rabbit aortic smooth muscle cells (SMC) and also the time of its action during the cell cycle. TGF-beta 1 at 10-10,000 pg/ml inhibited DNA synthesis of SMC in the G0 stage derived from normal media or atheromatous intima stimulated by either platelet-derived growth factor (PDGF), fibroblast growth factor, SMC-derived growth factor, or fetal bovine serum (FBS). TGF-beta 1 also inhibited the growth of SMC in the growing state stimulated by either PDGF or FBS. TGF-beta 1 was effective only when added to the culture within 2 h after stimulation of the G0 state SMC with PDGF. It also inhibited increase in transcription of the c-myc protooncogene on stimulation of SMC with PDGF. These data suggest that TGF-beta 1 inhibited proliferation of SMC irrespective of the cell phenotype, growth conditions, and growth factors present and that it exerted this inhibitory effect during the time of the G0/G1 transition.
Atherosclerosis 1991 Jun
PMID:Effects of transforming growth factor-beta 1 on growth of aortic smooth muscle cells. Influences of interaction with growth factors, cell state, cell phenotype, and cell cycle. 189 88

Platelet-derived growth factor (PDGF) is secreted by several cells that participate in the process of atherogenesis, including arterial wall monocyte-derived macrophages. Macrophages in human and non-human primate lesions have recently been demonstrated to contain PDGF-B chain protein in situ. In developing lesions of atherosclerosis, macrophages take up and metabolize modified lipoproteins, leading to lipid accumulation and foam cell formation. Oxidatively modified low density lipoproteins (LDL) have been implicated in atherogenesis and have been demonstrated in atherosclerotic lesions. The effects of the uptake of various forms of modified LDL on PDGF gene expression, synthesis, and secretion in adherent cultures of human blood monocyte-derived macrophages were examined. LDL oxidized in a cell-free system in the presence of air and copper inhibited the constitutive expression of PDGF-B mRNA and secretion of PDGF in a dose-dependent fashion. Oxidatively modified LDL also attenuated lipopolysaccharide-induced PDGF-B mRNA expression. These changes were unrelated to the mechanism of lipid uptake and the degree of lipid loading and were detectable within 2 h of exposure to oxidized LDL. The degree of inhibition of both basal and lipopolysaccharide-induced PDGF-B-chain expression increased with the extent of LDL oxidation. Monocyte-derived macrophages exposed to acetylated LDL or LDL aggregates accumulated more cholesterol than cells treated with oxidized LDL, but PDGF expression was not consistently altered. Thus, uptake of a product or products of LDL oxidation modulates the expression and secretion of one of the principal macrophage-derived growth factors, PDGF. This modulation may influence chemotaxis and mitogenesis of smooth muscle cells locally in the artery wall during atherogenesis.
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PMID:The influence of oxidatively modified low density lipoproteins on expression of platelet-derived growth factor by human monocyte-derived macrophages. 190 87

Pressure on the outside of arteries can cause physical and biochemical changes in the vessel wall of rabbits which are characteristic of atherosclerosis. It is hypothesized that occlusion of the vasa vasorum causes ischaemia of the arterial media which results in smooth muscle cell proliferation and cellular accumulation of cholesteryl esters. Hypoxia increases mRNA for platelet-derived growth factor in arterial wall cells and increases the activity of acyl CoA:cholesterol acyltransferase (ACAT). Such a mechanism may explain many of the anatomical, actuarial and environmental risk factors for atherosclerosis. Hypoperfusion may follow thrombosis of the vasa vasorum.
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PMID:Arterial wall hypoxia following thrombosis of the vasa vasorum is an initial lesion in atherosclerosis. 190 39

The increased growth potential of vascular smooth muscle cells (VSMCs) represents one of the crucial anomalies responsible for the development of essential hypertension, diabetic macroangiopathy, and atherosclerosis. The exaggerated response to growth factors of VSMC from spontaneously hypertensive rats (SHRs) persists in culture when compared with normotensive Wistar-Kyoto control rats, indicating an intrinsic defect in the hypertension-producing mechanism. This greater proliferation is characterized by two intermediate phenotypes: (1) accelerated entry into the S phase of the cell cycle, which results from hyperresponsiveness to epidermal growth factor and platelet-derived growth factor, and (2) abnormal contact inhibition. The enhanced expression of transforming growth factor beta 1 (TGF-beta 1) messenger ribonucleic acid in SHRs precedes this altered contact inhibition, and only VSMCs from SHRs respond to exogenously added TGF-beta 1 at a high cell density, which suggests that abnormal TGF-beta 1 autoregulation may be implicated in the second phenotype. Platelets contain major growth factors for VSMC. Platelet extracts from hypertensive and diabetic patients present augmented growth-promoting activity on VSMCs, which is most evident when both diseases occur simultaneously. Growth-promoting activity may be further influenced by antihypertensive therapy. This growth-promoting activity is increased by hydrochlorothiazide but not by indapamide, atenolol, or captopril in diabetic hypertensive and nondiabetic hypertensive patients. In conclusion, VSMCs in hypertension manifest an intrinsic growth defect that is modulated by extrinsic platelet growth factors and antihypertensive drugs.
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PMID:Vascular smooth muscle cell proliferation and its therapeutic modulation in hypertension. 192 87

The development of atherosclerosis includes an abnormal proliferation of smooth muscle cells (SMCs) in the arterial intima. The factors responsible for this process remain to be identified, but earlier studies have suggested that age-related changes in growth-regulatory mechanisms may be involved. In the present study growth-regulatory mechanisms of neonatal and adult rat SMCs have been compared both in early passage and after subcultivation. Neonatal SMCs in early passage were found to have a high rate of spontaneous DNA synthesis and showed little response to stimulation with growth factors. Early passage adult SMCs showed a lower rate of spontaneous DNA synthesis but responded well to exogenous growth factors. There was no difference in the gene or surface expression of receptors for platelet-derived growth factor (PDGF) between neonatal and adult cells, and there was no significant difference in the amount of inositol phosphate formed in the cells after stimulation with PDGF BB. However, there was increased expression of PDGF A chain mRNA in serum-starved neonatal cells as compared to adult serum-starved SMCs. After subcultivation (seven to nine passages) neonatal SMCs started to become senescent, had a low rate of spontaneous DNA synthesis and were more sensitive to growth factor stimulation than in early passage. Adult SMCs did not demonstrate signs of senescence after subcultivation. The results demonstrate marked differences in the mechanisms regulating growth of neonatal and adult rat SMCs and suggest that the increased sensitivity of adult cells to exogenous growth factors and the inability of these cells to become senescent may be important factors in atherogenesis.
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PMID:Differences in growth factor response in smooth muscle cells isolated from adult and neonatal rat arteries. 195 11


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