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 infiltration and activation of monocytes is a hallmark of chronic inflammation, including that associated with a variety of disease states such as rheumatoid arthritis, atherosclerosis, and various autoimmune conditions. Recently, a family of small molecular mass proteins has been described which appear to have inflammatory properties, including chemoattractant effects on monocytes. We report here on the molecular cloning, characterization, and functional expression of mu RANTES, a new murine member of this family. mu RANTES expressed in a mammalian expression system is an approximately 8-kDa protein exhibiting immune cross-reactivity with a rabbit polyclonal antiserum generated against human RANTES. Boyden chamber chemotaxis experiments reveal some lack of species specificity in monocyte chemoattractant potential, as recombinant mu RANTES attracts human monocytes in a dose-dependent fashion in vitro. mu RANTES and its human homolog share approximately 85% amino acid identity, a higher level of conservation than that seen with any other species homologs in this cytokine family, and second only to transforming growth factor-beta among reported immune cytokines.
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PMID:Molecular cloning and expression of the murine RANTES cytokine: structural and functional conservation between mouse and man. 137 60

While the roles of the platelet-derived growth factors (PDGFs) in vascular smooth muscle cells (SMCs) continue to be elucidated, these cells, especially in their activated 'synthetic' state, have also been found to express, and proliferate in response to, many of the other families of polypeptide growth factors, such as the fibroblast growth factors. Other stimulators of DNA synthesis, and particularly of SMC hypertrophy, include the vasoconstrictor hormones such as angiotensin II, as well as physical forces, especially stretch or tension. For many of these ligands, multiple receptors have been identified and their means of signal transduction are being characterized rapidly. Regulatory regions of these genes are being identified as are transcription factors. Complex post-transcriptional regulation has also been shown by the findings that some growth factors are phosphorylated, or translocated to the nucleus or the extracellular matrix. Inhibitors have also been identified. These include some prostaglandins, calcium antagonists, agonists that activate guanylate and adenylate cyclases, inhibitors of angiotensin-converting enzyme, interferon gamma, and heparin. Future studies are likely to show that tyrosine phosphatases and recessive oncogenes also regulate growth. The existence of so many autocrine/paracrine mitogens--together with some experimental data--suggests some redundancy in the system as well as some additive effects. Redundancy may limit the efficacy of antibodies to a single growth factor to block cell proliferation. Their evolutionary conservation implies some unique roles for each growth factor but these have not been apparent from in vitro studies to date. Further insights are apt to come from the increasing recognition that growth factors have other effects--on cell attachment, migration, survival, production of extracellular matrix, thrombosis, vaso-constriction, regulation of cytokine synthesis, and inhibition of growth. Many of these effects may prove to be context-dependent, as with the case of growth inhibition by transforming growth factor-beta. Studies in monolayer cultures may not obtain the same results as studies using cocultures of endothelial and smooth muscle cells, or 3-dimensional matrix cultures, organ cultures, or in the intact animal. In vivo descriptive studies of growth factors expressed in vascular embryogenesis, hypertension, atherosclerosis, acute balloon injury and thrombosis are being supplemented by interventions such as infusions with growth factors, antibodies, and toxin conjugates. These studies, and studies using transgenic mice and homologous recombination, should yield information as to mechanisms and may also suggest new therapies.
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PMID:Smooth muscle cell growth factors. 181 90

Bovine vascular smooth muscle cells (SMC) were examined for production of plasminogen activator inhibitor-1 (PAI-1) which may play a key role in regulating the fibrinolytic system. Growth-arrested SMC released active PAI (101 arbitrary units (AU)/10(6) cells/24 h) and a latent form of PAI (880 AU/10(6) cells/24 h) into the conditioned medium (CM). The levels of PAI were significant since 880 AU of PAI could inhibit approximately 1 microgram of tissue plasminogen activator. The extracellular matrix of SMC also contained PAI activity; however, the level was 17-fold less than that observed in the CM. SMC-PAI was a rapid inhibitor of tissue plasminogen activator (kass greater than 10(7) M-1 S-1) and was identified as a 45-kDa protein immunologically related to endothelial cell PAI-1. PAI-1 comprised 20 and 30%, respectively, of the newly synthesized protein detected in the CM and extracellular matrix of SMC. The SMC growth modulators, platelet-derived growth factor and transforming growth factor-beta, induced PAI-1 activity and protein synthesis by 2- and 3-fold, respectively, in a dose- and time-dependent manner. The increases in PAI-1 activity and protein synthesis were ascribed to elevated levels of PAI-1 mRNA as judged by Northern blot analysis of total RNA prepared from control and platelet-derived growth factor- and transforming growth factor-beta-treated cells. Increases in PAI-1 mRNA levels were evident 1 h after growth factor treatment and were maximal after 4 h. PAI-1 mRNA levels were unaffected by cycloheximide treatment. The results indicate that SMC synthesize and release PAI-1 which could regulate the normal fibrinolytic environment of the arterial wall. During atherosclerosis or after vascular injury increases in platelet-derived or locally produced mitogens may stimulate further PAI-1 synthesis and generate a prothrombotic state.
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PMID:Platelet-derived growth factor and transforming growth factor-beta regulate plasminogen activator inhibitor-1 synthesis in vascular smooth muscle cells. 203 43

Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. Recent evidence suggests that vasoconstrictive substances, such as angiotensin II (AII), may function as a vascular smooth muscle growth promoting substance. To explore the role of the counterregulatory hormone, atrial natriuretic polypeptide (ANP) in this process, we examined the effect of ANP (alpha-rat ANP [1-28]) on the growth characteristics of cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) significantly suppressed the proliferative effect of 1% and 5% serum as measured by 3H-thymidine incorporation and cell number, confirming ANP as an antimitogenic factor. In quiescent RASM cells, ANP (10(-7), 10(-6) M) significantly suppressed the basal incorporations of 3H-uridine and leucine by 50 and 30%, respectively. ANP (10(-7), 10(-6) M) also suppressed AII-induced RNA and protein syntheses (by 30-40%) with the concomitant reduction of the cell size. Furthermore, ANP also significantly attenuated the increase of 3H-uridine and leucine incorporations caused by transforming growth factor-beta (4 x 10(-11), 4 x 10(-10) M), a potent hypertrophic factor. These results indicate that ANP possesses an antihypertrophic action on vascular smooth muscle cells. Down-regulation of protein kinase C by 24-h treatment with phorbol 12,13-dibutyrate did not inhibit ANP-induced suppression on 3H-uridine incorporation. Based on the observation that ANP was more potent than a ring-deleted analogue of ANP on inhibiting 3H-uridine incorporation, we conclude that the ANP's inhibitory effect is primarily mediated via the activation of a guanylate cyclase-linked ANP receptor(s). Indeed 8-bromo cGMP mimicked the antihypertrophic action of ANP. Accordingly, we speculate that in addition to its vasorelaxant and natriuretic effects, the antihypertrophic action of ANP observed in the present study may serve as an additional compensatory mechanism of ANP in hypertension.
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PMID:Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells. 217 26

Migration of smooth muscle cells (SMC) in the arterial wall is important in the pathogenesis of atherosclerosis and is presumably regulated in both normal and atherosclerotic tissues. In this study, the effect of transforming growth factor-beta (TGF-beta) on the migration of rat aortic SMC was examined. TGF-beta alone enhanced the migration of SMC at concentrations of 10 to 50 pg/ml and its maximal effect was similar to that of platelet-derived growth factor (PDGF). Checker board analysis showed that TGF-beta had a chemotactic, but not a chemokinetic effect. PDGF also enhanced the migration in a dose-dependent manner and TGF-beta inhibited the PDGF-induced migration dose-dependently at 1.0 pg/ml to 1.0 ng/ml. These data suggest that TGF-beta is a bifunctional regulator of the migration of aortic SMC.
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PMID:Bifunctional effects of transforming growth factor-beta on migration of cultured rat aortic smooth muscle cells. 235 28

Transforming growth factor-beta, a peptide growth factor, is known to be a multifunctional regulator of cellular activity. The effect of this growth factor on extracellular matrix formation is well established, but its effects on elastin, a critical component of lung, skin, and blood vessels are unknown. In the present study, by use of an Enzyme-Linked Immunoassay method, we found that transforming growth factor-beta strongly increased elastin production in cultured porcine aortic smooth muscle cells. In a dosage-dependent study, 1.0-10.0 ng/ml transforming growth factor-beta promoted elastin production 2-3 fold. In a time-dependent study, at least an 8 h pre-treatment with 10.0 ng/ml transforming growth factor-beta was required for sustained increases in elastin production. The effects of transforming growth factor-beta on cultured aortic smooth muscle cells suggest that this cytokine may be an important mediator of elastin formation during atherosclerosis and hypertension.
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PMID:The elastogenic effect of recombinant transforming growth factor-beta on porcine aortic smooth muscle cells. 316 37

Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin are inducible proteins involved in cell-cell adhesion. Immunohistochemical studies have indicated that human atherosclerotic plaques contain smooth muscle cells (SMCs) that express ICAM-1 and VCAM-1. Recently, we demonstrated that SMCs in culture express a functionally active cytokine-inducible ICAM-1. SMCs and mononuclear cells participate in the local accumulation of cytokines and related growth factors in atherosclerotic lesions. Therefore, we determined the effects of different cytokines and growth factors on mRNA content and cell surface expression of VCAM-1, ICAM-1, and E-selectin in cultured human aortic SMCs by Northern blotting, quantitative polymerase chain reaction amplification, and immunofluorescence flow cytometry. Under basal conditions of cultivation, both VCAM-1 mRNA and membrane expression of VCAM-1 were low and were induced very little by interleukin-1 beta (100 U/mL). Platelet-derived growth factor or transforming growth factor-beta decreased VCAM-1 mRNA basal expression. Treatment of SMCs with tumor necrosis factor-alpha (TNF-alpha) led to an increase in both VCAM-1 mRNA and cell surface expression for VCAM-1 in a dose- and time-dependent manner. Interferon-gamma induced a weak increase in VCAM-1 mRNA expression, with no synergistic effect on the stimulation by TNF-alpha. Various differences were noted between the expression of ICAM-1 and VCAM-1 genes, because interleukin-1 beta induced substantial amounts of ICAM-1 but not VCAM-1. The addition of interferon-gamma delays the time at which peak expression of ICAM-1 in response to TNF-alpha stimulation occurs. Under our conditions, we did not detect any expression of E-selectin by SMCs. These results suggest that cytokines regulate VCAM-1 and ICAM-1 expression on arterial SMCs and could play an important role in the pathophysiology of inflammatory and immune processes in atherosclerosis.
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PMID:Regulation of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular smooth muscle cells. 750 14

Recent evidence has led us to propose that transforming growth factor-beta (TGF-beta) is a key inhibitor of atherosclerosis. We show here that a population of patients with advanced atherosclerosis all have less active TGF-beta in their sera than patients with normal coronary arteries, with a fivefold difference in average concentration between the two groups. This correlation with atherosclerosis is much stronger than for other known major risk factors and it may therefore have important diagnostic and prognostic significance. Aspirin medication correlates with an increase in active TGF-beta concentration, indicating that therapeutic interventions for TGF-beta are possible.
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PMID:The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. 758 46

Accumulation of oxidized low density lipoproteins in macrophages and smooth muscle cells causes foam cell formation, an initial step in atherosclerosis. Active oxygen species are considered important in the pathogenesis of the disease. Antioxidants, such as tocopherols and tocotrienols have been considered to prevent the deleterious effects of active oxygen species. We found native low density lipoproteins can stimulate directly smooth muscle cell proliferation, it is associated with an increase of protein kinase C activity. d-alpha-Tocopherol, biologically most active form of vitamin E, inhibits both cell proliferation and protein kinase C activity. The effect of d-alpha-tocopherol is not related to its radical scavenging properties. Transforming growth factor-beta secreted by smooth muscle cells as growth inhibitor. Low density lipoproteins decrease the release of transforming growth factor-beta from smooth muscle cells thus activating growth. d-alpha-Tocopherol activates the cellular release of transforming growth factor-beta. These new aspects explain the important role of low density lipoproteins and vitamin E in increasing and decreasing the risk of atherosclerosis, respectively.
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PMID:New roles of low density lipoproteins and vitamin E in the pathogenesis of atherosclerosis. 773 26

Most large studies of the blood parameters that act as risk factors for myocardial infarction, stroke and atherosclerosis have identified elevated circulating levels of lipoprotein(a) as an important risk factor. Lipoprotein(a) consists of an LDL particle that is covalently bound to the distinguishing protein component apolipoprotein(a). Ever since apolipoprotein(a) was cloned in 1987 and the marked sequence homology to plasminogen was noted, mechanisms for the atherogenic activity of lipoprotein(a), based on the competitive inhibition of plasminogen activity, have been proposed. However, with the availability of transgenic mice expressing both human apolipoprotein(a) and lipoprotein(a), recent studies have demonstrated that lipoprotein(a) acts to inhibit plasminogen activation in vivo. One consequence of this is reduced activation of the cytokine transforming growth factor-beta, an important regulator of vessel wall structure.
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PMID:Transforming growth factor-beta: the key to understanding lipoprotein(a)? 777 72


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