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)

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

Lipoprotein lipase (LPL), which is secreted by the two predominant cell types in atherosclerotic plaque, macrophages and smooth muscle cells, may be involved in atherosclerosis by generating atherogenic remnant lipoproteins. We investigated the effects of platelet-derived growth factor (PDGF)-BB on the synthesis of LPL by human monocyte-derived macrophages. These cells were cultured in the presence of PDGF-BB for 8 days, after which the enzyme activity, mass, and mRNA levels of LPL were determined. The effect of PDGF-BB was time-dependent and dose-dependent at concentrations of 1 to 10 ng/mL. At 10 ng/mL PDGF-BB enhanced twofold to 2.3-fold the secretion of LPL, and a pulse-labeling study with [35S]methionine revealed that 10 ng/mL PDGF-BB significantly increased the synthesis of LPL. Northern blotting analysis showed that the LPL mRNA level increased dose dependently in macrophages treated with PDGF-BB, and 10 ng/mL PDGF-BB enhanced twofold the expression of LPL mRNA. The protein kinase C inhibitor staurosporine suppressed the effect of PDGF-BB on LPL activity. These results indicate that PDGF-BB stimulated transcription of the LPL gene in human monocyte-derived macrophages through protein kinase C activation and resulted in an increased synthesis of LPL. Therefore, we hypothesize that the augmented synthesis of LPL by PDGF-BB modulates atherosclerosis by influencing lipoprotein metabolism in the vascular wall.
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PMID:Effects of platelet-derived growth factor on the synthesis of lipoprotein lipase in human monocyte-derived macrophages. 774 65

The effects of lysophosphatidylcholine (LPC), a vasoactive phospholipid, on intracellular free calcium concentration ([Ca2+]i), DNA synthesis and cytotoxicity of vascular smooth muscle cells (VSMC) were studied. LPC from 10(-7) to 10(-5) mol/l dose-dependently induced a sustained increase in [Ca2+]i. In contrast to the response of [Ca2+]i induced by angiotensin II, that induced by LPC was totally abolished when extracellular Ca2+ was removed, was not affected by pretreatment of the cells with islet-activating protein, and was not desensitized by repeated addition. 8-(N,N-Diethylamino)octyl 3,4,5-trimethoxybenzoic acid (TMB-8), an inhibitor of Ca2+ release from intracellular Ca2+ stores, 1-(5-isoquinolinesulfonyl)-2-methylpiperadine dihydrochloride (H-7), an inhibitor of protein kinase C, KT5823, an inhibitor of protein kinase G, and Ca2+ channel blockers failed to suppress the LPC-induced increase in [Ca2+]i. LPC at 10(-5) mol/l caused significant stimulation of [3H]thymidine incorporation into VSMC, and at concentrations of 10(-5) mol/l and higher dose-dependently stimulated release of lactate dehydrogenase in cell culture supernatants. Moreover, digitonin mimicked the effects of LPC on [Ca2+]i, and also caused similar effects to those of LPC on DNA synthesis and cytotoxicity in VSMC. These observations suggest that LPC causes both cell growth and cell injury of VSMC, at least partly, through its detergent action, causing membrane leakiness and resultant [Ca2+]i overload in vitro, thus indicating the possible participation of LPC in atherosclerosis and/or injury of the vascular wall.
Atherosclerosis 1995 Jan 06
PMID:Lysophosphatidylcholine causes Ca2+ influx, enhanced DNA synthesis and cytotoxicity in cultured vascular smooth muscle cells. 777 68

To define the physiological roles of elastase in the vascular wall, we examined whether elastase at low concentrations can modulate the proliferation of vascular smooth muscle cells (VSMC). Elastase itself at low concentrations from 1 to 50 ng/ml inhibited DNA synthesis dose-dependently in VSMC. However, phenylmethylsulfonyl fluoride-inactivated elastase failed to induce this inhibition. OP-41483, a stable analogue of prostacyclin, inhibited DNA synthesis and stimulated accumulation of cAMP in VSMC. Preincubation of VSMC for 24 h with 50 ng/ml elastase enhanced both inhibition of DNA synthesis and the accumulation of cAMP induced by OP-41483. Preincubation of VSMC with 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C (PKC), also enhanced cAMP accumulation induced by OP-41483. On the other hand, elastase failed to enhance OP-41483-induced cAMP accumulation in PKC down-regulated cells. Furthermore, coincubation with chelerythrine, an inhibitor of PKC, inhibited the enhancement of cAMP accumulation induced by preincubation with elastase. These results suggest that elastase at low concentrations can enhance the inhibition of VSMC proliferation induced by prostacyclin through the activation of protein kinase C.
Atherosclerosis 1994 Sep 30
PMID:Elastase enhances cAMP accumulation and the inhibition of DNA synthesis induced by OP-41483, a stable prostacyclin analogue, in vascular smooth muscle cells. 785 65

In the past decade it has become apparent that many diseases result from aberrations in signaling pathways. These include proliferative diseases such as cancers, atherosclerosis and psoriasis and inflammatory conditions such as sepsis, rheumatoid arthritis and tissue rejection. These findings refocused the research of the medical community to seek new modalities for disease management which essentially consist of designing drugs which intercept cell signaling. In this review, the emerging success in using tyrosine kinase blockers and other signal interceptors, such as protein kinase C blockers, Ras blockers, Ca2+ signaling inhibitors and estrogen antagonists which inhibit growth of cancer cells in vitro and in vivo, will be discussed. These signal interceptors, especially tyrosine-kinase blockers, are also able to block inflammatory responses and the proliferation of vascular smooth muscle cells and psoriatic keratinocytes. The utility of signal interceptors in analyzing signal-transduction pathways is also discussed.
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PMID:Signal-transduction therapy. A novel approach to disease management. 795 36

Over the past several decades emphasis has been given to the elucidation of mechanisms involved in the onset and progression of cardiovascular disorders. Stroke, hypertension, and atherosclerosis continue to rank as primary causes of death in the western world. In the case of atherosclerosis, the preferential localization of atheroma to large- and medium-sized blood vessels and the sequence of events leading to plaque development have been well defined. Damage to luminal endothelial and/or medial smooth muscle cells, migration of inflammatory cells, diffusion or local delivery of mediators within the vessel wall, proliferation of vascular smooth muscle cells, and cellular accumulation of lipids are now recognized as hallmarks of the pathologic process. Although these events have been established with a fair degree of certainty, the mechanisms responsible for initiation of the atherosclerotic process are not yet completely understood. Environmental chemicals have come under increasing scrutiny as evidence continues to accumulate suggesting that toxic insult plays an important role in the initiation and/or progression of atherosclerotic disorders. This review focuses on various aspects of xenobiotic-induced vascular injury with emphasis on the toxic effects of allylamine and benzo[a]pyrene in smooth muscle cells, the primary cellular component of atherosclerotic lesions. Both of these chemicals modulate growth and differentiation programs in aortic smooth muscle cells and have been implicated in the development of atherosclerotic-like lesions in laboratory animals. The major findings from recent studies examining the cellular and molecular basis of toxicant-induced phenotypic modulation of vascular smooth muscle cells to a proliferative state and the role of oxidative metabolism, phospholipid turnover, protein kinase C, ras-related signal transduction, and matrix interactions in the vasculotoxic response to allylamine and benzo[a]pyrene are discussed.
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PMID:Responses of vascular smooth muscle cells to toxic insult: cellular and molecular perspectives for environmental toxicants. 799 Jan 68

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

The activities of protein kinase C, total, Mg2 and Na+, K(+)-dependent ATPases in red cell membranes were compared in 46 patients with insulin independent, 30 ones with insulin dependent diabetes mellitus with various degrees of vascular disorders, and in 17 patients with atherosclerosis with the predominant involvement of the main vessels of the lower limbs. Diabetes mellitus and the progress of vascular disorders were associated with a more marked depression of protein kinase C, total and Na+, K(+)-dependent ATPase activities, this being particularly characteristic of the patients with insulin-independent diabetes and macrovascular disorders. Inhibited activities of protein kinase C and ATPases in red cell membranes in the course of diabetic vascular disorders progress evidence their contribution to the pathogenesis of diabetic angiopathy.
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PMID:[Activity of membrane-bound protein kinase C and ATPase in erythrocytes in diabetic angiopathy]. 805 53

Alterations of vascular smooth muscle cell (VSMC) proliferation have been implicated in the age-dependent susceptibility to atherosclerosis. Although it is known that protein kinase C (PKC) is involved in the mechanism of VSMC proliferation, there are no data on the possible involvement of PKC in disregulating VSMC proliferation in aged vascular cells. We evaluated the proliferative pattern, the PKC responsiveness and the effect of phorbol ester (PMA) treatment on vascular cell growth and cell cycle distribution in VSMCs from young and aged rats. The proliferative response was significantly higher in aged than in young cells after serum stimulation (7.5 vs. 2.8 x 10(4), 18 vs. 12 x 10(4), 26 vs. 22 x 10(4) cells/well, aged vs. young at days 2, 4, 6; P < 0.005). On the contrary, aged cells showed a significant inhibition of DNA synthesis at 48 h incubation with PMA concentrations of 1, 10, 100 nM (-47%, -53%, -58%, respectively) compared with controls (fetal calf serum 0.5%) and cell count (average decrease: -38% from 48 h to 96 h) after treatment with PMA 10 nM. The opposite was observed in young cells on [3H]thymidine incorporation with PMA 1, 10, 100 nM (+52%, +100%, +121%, respectively and cell count (average increase +55% from 48 h to 96 h). In addition, inhibition of the cell cycle from G1 to the S phase and reduction of PKC translocation in aged VSMC were observed. Alterations of PKC function could be involved in the disregulation of aged VSMC proliferation, which seems to characterize the increased susceptibility to atherosclerosis.
Atherosclerosis 1993 Dec
PMID:Protein kinase C pathway and proliferative responses of aged and young rat vascular smooth muscle cells. 814 37

High blood pressure is one of the major risk factors for atherosclerosis. In this study, we examined the effects of pressure on cell proliferation and DNA synthesis in cultured rat vascular smooth muscle cells. Pressure without shear stress and stretch promotes cell proliferation and DNA synthesis in a pressure-dependent manner. Pressure-induced DNA synthesis was inhibited significantly by the phospholipase C (PLC) inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, the protein kinase C inhibitor H-7, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine, staurosporine, and the tyrosine kinase inhibitor ([3,4,5-trihydroxyphenyl]methylene)propanedinitrile. To clarify whether activation of PLC and calcium mobilization are involved in pressure-induced DNA synthesis, production of 1,4,5-inositol trisphosphate (IP3) and intracellular Ca2+ was measured. Pure pressure increased IP3 and intracellular Ca2+ in a pressure-dependent manner. The increases in both IP3 and intracellular Ca2+ were inhibited significantly by 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate. This study demonstrates a novel cellular mechanism whereby pressure regulates DNA synthesis in vascular smooth muscle cells, possibly via activation of PLC and protein kinase C.
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PMID:Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells. 818 28


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