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

Glucose transport activity in cultured rat vascular smooth muscle cells (VSMCs) was examined under various concentrations of D-glucose, insulin, and insulin-like growth factor-I (IGF-I). Confluent cultures of VSMCs were incubated with serum-free medium containing 0-25 mmol/l of D-glucose for 24-49 h. The basal rate of 2-deoxyglucose uptake was reduced in association with increasing concentrations of D-glucose. Uptake of 2-deoxyglucose into the cells was linear between 0 and 15 min of incubation regardless of the glucose concentration. The uptake was inhibited by the addition of 10 mumol/l cytochalasin B or 100 mmol/l D-glucose indicating that the effects were mediated by specific integral glucose carriers. The effect of D-glucose was time-dependent and reversible. Insulin increased the uptake of 2-deoxyglucose in a dose-dependent manner, and its effect was dependent on the preincubation dose of D-glucose. Insulin-stimulated uptake was lower in the cells pre-exposed to 25 mmol/l D-glucose than in the cells pre-exposed to concentrations of D-glucose below 5.5 mmol/l. After a long-term incubation with insulin, the insulin-stimulated glucose transport was inhibited. Recovery of glucose transport activity was assessed by incubating cells with D-glucose for 24-48 h to induce desensitization. After a 24 h glucose conditioning, the uptake of 2-deoxyglucose was lower in the cells preincubated with 25 mmol/l glucose than in the cells preincubated with 5.5 mmol/l glucose. The effect of the glucose conditioning was reversible and dependent on the preincubation dose of D-glucose. IGF-I was a more potent stimulator of glucose transport than insulin. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), inhibited the uptake of glucose stimulated by insulin or IGF-I in a dose-dependent manner. Our results suggest that D-glucose regulates its own uptake independently of insulin and modulates the ability of insulin to induce insulin resistance in the cultured rat VSMCs. Glucose attenuated the effect of insulin, and led to a progressive decrease in the activity of the glucose transport effector system. Activation of wortmannin-sensitive PI3-kinase may be involved in the signaling pathways of the insulin- and IGF-I-stimulated glucose uptake in VSMCs. This mechanism of insulin resistance may be relevant to the formation of cellular defects in the vascular wall in patients with diabetes mellitus.
Atherosclerosis 1996 Nov 15
PMID:Effect of glucose, insulin, and insulin-like growth factor-I on glucose transport activity in cultured rat vascular smooth muscle cells. 900 4

Hyperinsulinemia (HI) and insulin resistance (IR) are frequently associated with hypertension and atherosclerosis. However, the exact roles of HI and IR in the development of hypertension are unclear. Mitogen-activated protein kinases (MAPK) are well-characterized intracellular mediators of cell proliferation. In this study, we examined the contribution of MAPK pathway in insulin-stimulated mitogenesis using primary vascular smooth muscle cells (VSMCs) isolated from aortas of normotensive Wistar-Kyoto rats (WKY) and spontaneous hypertensive rats (SHR). VSMCs were grown to confluence in culture, serum starved, and examined for DNA synthesis (using [3H]thymidine (TDR), immunoprecipitated MAPK activity, and MAPK phosphatase (MKP-1) induction). Basal rate of TDR incorporation into DNA was twofold higher in SHR compared with WKY (P < 0.005). Insulin caused a dose-dependent increase in TDR incorporation (150% over basal levels with 100 nM in 12 h). Stimulation was sustained for 24 h with a decline toward basal in 36 h. Pretreatment with insulin-like growth factor I (IGF-I) receptor antibody did not abolish mitogenesis mediated by 10-100 nM insulin, suggesting that insulin effect is mediated via its own receptors. Insulin had a small mitogenic effect in WKY (33% over basal). Insulin-stimulated mitogenesis was accompanied by a dose-dependent increase in MAPK activity in SHR, with a peak activation (>2-fold over basal) between 5 and 10 min with 100 nM insulin. Insulin had very small effects on MAPK activity in WKY. In contrast, serum-stimulated MAPK activation was comparable in WKY and SHR. Pretreatment with MEK inhibitor, PD-98059, completely blocked insulin's effect on MAPK activation and mitogenesis. Inhibition of phosphatidylinositol 3-kinase with wortmannin also prevented insulin's effects on MAPK activation and mitogenesis. In WKY, insulin and IGF-I treatment resulted in a rapid induction of MKP-1, the dual-specificity MAPK phosphatase. In contrast, VSMCs from SHR were resistant to insulin with respect to MPK-1 expression. We conclude that insulin is mitogenic in SHR, and the effect appears to be mediated by sustained MAPK activation due to impaired insulin-mediated MKP-1 mRNA expression, which may act as an inhibitory feedback loop in attenuating MAPK signaling.
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PMID:Vascular smooth muscle cell growth and insulin regulation of mitogen-activated protein kinase in hypertension. 968 33

Phosphorylated tyrosine residues of growth factor receptors that associate with intracellular proteins containing src-homology 2 (SH2) domains are integral components in several signal transduction pathways related to proliferative diseases such as cancer, atherosclerosis, and restenosis. In particular, a phosphorylated pentapeptide [pTyr751-Val-Pro-Met754-Leu (pTyr = phosphotyrosine)] derived from the primary sequence of platelet-derived growth factor-beta (PDGF-beta) receptor blocks the association of the C-terminal SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) to PDGF-beta receptor with an IC50 of 0.445 +/- 0.047 microM. Further evaluation of the structure-activity relationships for pTyr751-Val-Pro-Met-Leu resulted in the design of smaller peptidomimetics with enhanced affinity including Ac-pTyr-Val-Ala-N(C6H13)2 (IC50 = 0.076 +/- 0.010 microM). In addition, the phosphotyrosine residue was replaced with a difluorophosphonate derivative [4-phosphono(difluoromethyl)phenylalanine (CF2Pmp)] which has been shown to be stable to cellular phosphatases. The extracellular administration of either CF2Pmp-Val-Pro-Met-Leu or Ac-CF2Pmp-Val-Pro-Met-NH2 in a whole cell assay resulted in specific inhibition of the PDGF-stimulated association from the C-terminal SH2 domain of the p85 subunit of PI 3-kinase to the PDGF-beta receptor in a dose-dependent manner. These compounds were also effective in inhibiting GLUT4 translocation, c-fos expression, and cell membrane ruffling in single-cell microinjection assay.
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PMID:Design of peptidomimetics that inhibit the association of phosphatidylinositol 3-kinase with platelet-derived growth factor-beta receptor and possess cellular activity. 978 8

Proliferation of vascular smooth muscle cells contributes to initimal hyperplasia during atherogenesis, but the factors regulating their proliferation are not well known. In the present study we report that sublytic C5b-9 assembly induced proliferation of differentiated human aortic smooth muscle cells (ASMC) in culture. Cell cycle re-entry occurred through activation of cdk4, cdk2 kinase and the reduction of p21 cell cycle inhibitor. We also investigated if C5b-9 cell cycle induction is mediated through activation of mitogen activated protein kinase (MAPK) pathways. Extracellular signal regulated kinase (ERK) 1 activity was significantly increased, while c-jun NH2-terminal kinase (JNK) 1 and p38 MAPK activity were only transiently increased. Pretreatment with wortmannin inhibits ERK1 activation by C5b-9, suggesting the involvement of phosphatidylinositol 3-kinase (PI 3-kinase). Both PI 3-kinase and p70 S6 kinase were activated by C5b-9 but not by C5b6. C5b-9 induced DNA synthesis was abolished by pretreatment with inhibitors of ERK1 and PI 3-kinase, but not by p38 MAPK. These data indicated that ERK1 and PI 3-kinase play a major role in C5b-9 induced ASMC proliferation.
Atherosclerosis 1999 Jan
PMID:Sublytic C5b-9 induces proliferation of human aortic smooth muscle cells: role of mitogen activated protein kinase and phosphatidylinositol 3-kinase. 992 May 5

Chemokines are chemotactic cytokines that activate and direct the migration of leukocytes. However, their role in modulating platelet function has not been shown. We studied the direct effect of chemokines on human platelets and found that of the 16 tested only stromal cell-derived factor (SDF)-1 induced platelet aggregation, accompanied by a rise in intracellular calcium. Platelets expressed the SDF-1 receptor, CXCR4, and an antibody to CXCR4 and pertussis toxin inhibited SDF-1-induced platelet aggregation, confirming that this effect is mediated through CXCR4, a Galphai-coupled receptor. SDF-1-induced platelet aggregation was also inhibited by wortmannin, LY294002, and genistein, suggesting that phosphatidylinositol 3-kinase and tyrosine kinase are likely involved in SDF-1-induced platelet aggregation. Because chemokines are produced from multiple vascular cells and atherosclerotic vessels are prone to develop platelet-rich thrombi, we examined the expression of SDF-1 in human atheroma. SDF-1 protein was highly expressed in smooth muscle cells, endothelial cells, and macrophages in human atherosclerotic plaques but not in normal vessels. Our studies demonstrate a direct effect of a chemokine in inducing platelet activation and suggest a role for SDF-1 in the pathogenesis of atherosclerosis and thrombo-occlusive diseases.
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PMID:The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. 1066 7

There is a very close interrelationship between the metabolic disorders such as obesity and diabetes mellitus and cardiovascular diseases such as hypertension and atherosclerosis, with insulin resistance and endothelial dysfunction as common features. Insulin has vasculoprotective effects through production of nitric oxide in the endothelial cells, while it produces atherogenic effects by stimulating proliferation and migration of vascular smooth muscle cells(VSMC). The insulin-activated pathway is the phosphatidylinositol 3-kinase pathway in the endothelial cells and MAP kinase pathway in the VSMC. Insulin resistance and hyperinsulinemia may result in the attenuation of the endothelium-mediated action and stimulation of the VSMC-mediated action. Insulin resistance and endothelial dysfunction are related to each other and may cause vicious cycle, leading to the metabolic and cardiovascular diseases.
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PMID:[Insulin resistance and vascular function]. 1070 56

Occlusive accelerated atherosclerosis of coronary grafts is the predominant factor that limits longevity of heart transplant recipients. This form of vascular disease affects both the large epicardial and the smaller intramyocardial vessels, leading to characteristic clinical presentation that necessitates the use of sophisticated techniques for their accurate detection. Accelerated atherosclerosis after transplantation is a multifactorial disease with many events contributing to its progression. The initial vascular injury associated with ischemia-reperfusion appears to aggravate preexisting conditions in the donor vasculature in addition to activation of new immunological and nonimmunological mechanisms. Throughout these events, the endothelium remains a primary target of cell- and humoral-mediated injury. Changes in the vascular intima leads to alterations in vascular smooth muscle cell (VSMC) physiology, resulting in VSMC phenotypic modulation with the orchestration of a broad spectrum of growth and inflammatory reactions, which might be a healing response to vascular injury. Endogenous nitric oxide (NO) pathways regulate a multiplicity of cellular mechanisms that play a major role in determining the structure and function of the vessel wall during normal conditions and during remodeling associated with accelerated atherosclerosis. Recently identified signaling pathways, including mitogen-activated protein kinase, cGMP-dependent protein kinase, phosphatidylinositol 3-kinase, and transcriptional events in which nuclear factor kappa B and activator protein 1 take part, can be associated with NO modulation of cell cycle perturbations and phenotypic alteration of VSMC during accelerated atherosclerosis. This article reviews recent progress covering the aforementioned matters. We start by summarizing the clincal aspects and pathogenesis of accelerated atherosclerosis associated with transplantation, including clinical presentation and detection. This summary is followed by a discussion of the multiple factors of the disease process, including immunological and nonimmunolgical contributions. The next section focuses on cellular responses of the VSMCs relevant to lesion formation, with special emphasis on classical and recent paradigms of phenotypic modulation of these cells. To examine the influence of NO on VSMC phenotypic modulation and consequent lesion development, we briefly overview characteristics of NO production in the normal coronary vascular bed and the changes in endogenous NO release and activity during atherosclerosis. This overview is followed by a section covering molecular mechanisms whereby NO regulates a range of signaling pathways, transcriptional events underlying cell cycle perturbation, and phenotypic alteration of VSMC in accelerated atherosclerosis.
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PMID:Transplant atherosclerosis: role of phenotypic modulation of vascular smooth muscle by nitric oxide. 1097 14

Oxidized LDL can induce an increase in intracellular calcium concentration and the activation of protein kinase C in mouse peritoneal macrophages. The activation of protein kinase C leads to the release into the culture medium of granulocyte-macrophage colony-stimulating factor, which plays a priming role in oxidized LDL-induced macrophage proliferation. The expression of granulocyte-macrophage colony-stimulating factor in macrophages by oxidized LDL is positively regulated in the 5'-flanking region of granulocyte-macrophage colony-stimulating factor gene from sequence -169 to -160, but negatively regulated from -91 to -82. Granulocyte-macrophage colony-stimulating factor released by oxidized LDL from macrophages induces proliferation in autocrine or paracrine fashion via the activation of phosphatidylinositol 3-kinase. The capacity of oxidized LDL to induce macrophage proliferation in vitro may be involved in the enhanced progression of atherosclerosis in vivo.
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PMID:Macrophage proliferation in atherosclerosis. 1104 93

Abnormal vascular smooth muscle cell (VSMC) growth plays a key role in the pathogenesis of hypertension and atherosclerosis. Angiotensin II (ANG II) elicits a hypertrophic growth response characterized by an increase in protein synthesis without cell proliferation. The present study investigated the role of the nonreceptor tyrosine kinase PYK2 in the regulation of ANG II-induced signaling pathways that mediate VSMC growth. Using coimmunoprecipitation analysis, the role of PYK2 as an upstream regulator of both extracellular signal-related kinase (ERK) 1/2 mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI 3-kinase) pathways was examined in cultured rat aortic VSMC. ANG II (100 nM) promoted the formation of a complex between PYK2 and the ERK1/2 regulators Shc and Grb2. ANG II caused a rapid and Ca(2+)-dependent tyrosine phosphorylation of the adapter molecule p130Cas, which coimmunoprecipitated both PYK2 and PI 3-kinase in ANG II-treated VSMC. Complex formation between PI 3-kinase and p130Cas and PYK2 was associated with a rapid phosphorylation of the ribosomal p70(S6) kinase in a Ca(2+)- and tyrosine kinase-dependent manner. These data suggest that PYK2 is an important regulator of multiple signaling pathways involved in ANG II-induced VSMC growth.
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PMID:A role for PYK2 in regulation of ERK1/2 MAP kinases and PI 3-kinase by ANG II in vascular smooth muscle. 1112 80


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