Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human atherosclerotic plaques are heterogeneous tissues containing a number of different cell types, including macrophages, smooth muscle, endothelial and other undefined mesenchymal-appearing cells. Significant numbers of macrophages are found in human atherosclerotic plaques and have been postulated to be a major source of growth factor production during atherogenesis. In vitro evidence suggested that macrophages synthesize PDGF and might therefore contribute to the growth of the vessel wall in atherosclerosis. However, examination of PDGF synthesis in human atheroma by in situ hybridization revealed that while smooth muscle, mesenchymal, and endothelial cells synthesize this growth factor macrophages did not. Our inability to detect PDGF mRNA in macrophages was not due to any problems with hybridization to this cell type. In situ hybridization studies on human atherosclerotic plaques have demonstrated that plaque macrophages contain many different mRNAs other than PDGF including tissue factor, factor XIII, apoprotein E, transforming growth factor beta, and tumor necrosis factor. Recent studies have indicated that macrophages may be a major source as well of another group of inflammatory cytokines which are members of the RANTES/SIS cytokine family. In situ hybridization studies on human carotid endarterectomy specimens using probes specific for the inflammatory cytokines RANTES, LD78, HIMAP, and MCP-1 revealed numerous cells containing the mRNAs encoding for these proteins (5%, 13%, 8%, and 16% of plaque cells respectively). This is in contrast to generally low level expression found in normal human arteries (< 1% of normal medial cells contain these mRNAs). Cells expressing these cytokines were often found associated with inflammatory zones in human atherosclerotic plaques. Serial section immunohistochemistry suggests that macrophages and/or T cells may synthesize these proteins. In addition to localization to macrophages MCP-1 expression was also detected in smooth muscle cells and mesenchymal-appearing cells with many of the morphological characteristics of cells previously seen to express PDGF. In vitro evidence suggests that these proteins may be chemotactic to monocytes and lymphocytes. The finding of increased expression of these mRNAs in human atheroma suggests they may play a role in monocyte trafficking into the atherosclerotic plaque.
 ...
PMID:Local expression of inflammatory cytokines in human atherosclerotic plaques. 922 84

This article reviews recent advances in the effects of estrogen on bone and other body systems. The effect of estrogen use for the prevention of osteoporosis is no longer a matter of debate. Some issues are still discussed, however, especially with regard to the magnitude of its protection (especially for hip fracture), which would be dependent on the time at which estrogen therapy is initiated with respect to menopause as well as its total duration of use. The mechanisms of estrogen's action on bone also remains poorly understood. Controversy persists concerning the specific contribution of an indirect action through the modulation of calciotropic hormones and a direct action on bone cells in which estrogen receptors have been identified. Estrogens have been shown to reduce osteoclastogenesis by modulating the production of cytokines (interleukins, tumor necrosis factor) and transforming growth factor from bone marrow and bone cells. In addition to its effects on bone, a great number of observational studies have evaluated the relationship between estrogen use and coronary heart disease. The overall risk of coronary disease is estimated to be reduced by 50% in women who use estrogen replacement therapy. This reduction would be even greater in women with previous atherosclerosis. Moreover, recent data suggest that estrogen use could be associated with delayed onset and reduced risk for Alzheimer's disease. Overall, estrogen treatment in postmenopausal women has several proven benefits. Conversely, the potential risks of long-term estrogen therapy include a slightly increased risk of breast cancer, which would be associated with long-term use. Although the individual decision for a postmenopausal woman to start estrogen replacement therapy must take into account this risk:benefit ratio, current evidence suggests a clear advantage for estrogen's benefits over its risks.
 ...
PMID:Effect of estrogens on bone and other systems and hormonal substitute treatment. 922 84

In vitro-studies have shown that phospholipid hydrolysis of low density lipoproteins (LDL) by bee venom or porcine pancreatic phospholipase A2 (PLA2) leads to an increased uptake of these lipoproteins by macrophages transforming them into foam cells. Recently, a secretory phospholipase A2, group II, was detected in human atherosclerotic plaques. In order to investigate the role of this enzyme in the pathogenesis of atherosclerosis, a structurally identical human secretory PLA2 was purified from the medium of HepG2 cells stimulated with interleukin-6 and tumor necrosis factor-alpha. The activity of the purified enzyme towards the phospholipids of native and modified low density lipoproteins was compared with the activity towards Escherichia coli-membranes and other phospholipid substrates. Compared to E. coli-membranes, native LDL proved to be a poor substrate for group II PLA2. After mild oxidation induced by copper ions or by 2,2-azobis(2-amidinopropane) (AAPH), the susceptibility of LDL to phospholipid hydrolysis was found to be increased by 25 and 23%, respectively, whereas extensive copper-mediated oxidation caused a decreased hydrolysis. Aging of LDL at 6 degrees C for weeks or at 37 degrees C for hours resulted in an increase in PLA2-catalyzed phospholipid hydrolysis of up to 26-fold. LDL protected from oxidation by probucol during aging showed a lesser increase in susceptibility to phospholipid hydrolysis. Our results suggest that PLA2, group II, can increase the atherogenicity of LDL by its ability to hydrolyze the phospholipids of these lipoproteins, especially after modifications that are likely to occur in vivo.
Atherosclerosis 1997 Jul 25
PMID:Minimal oxidation and storage of low density lipoproteins result in an increased susceptibility to phospholipid hydrolysis by phospholipase A2. 924 62

Oxygen free radicals (OFRs) have been implicated in the development of hypercholesterolemic atherosclerosis. Flax seed is the richest source of omega-3 fatty acid and lignans. omega-3 Fatty acid suppresses the production of interleukin-1 (IL-1), tumor necrosis factor (TNF) and leukotriene B4 (LTB4), and of OFRs by polymorphonuclear leukocytes (PMNLs) and monocytes. Lignans possess anti-platelet activating factor (PAF) activity and are antioxidant. PAF, IL-1, TNF and LTB4 are known to stimulate PMNLs to produce OFRs. Flaxseed would, therefore, reduce the levels of OFRs and hence would prevent the development of hypercholesterolemic atherosclerosis. The effects of dietary flax seed on a high cholesterol diet induced atherosclerosis, lipid profile and OFR-producing activity of PMNLs (PMNL-CL) were investigated in rabbits. The rabbits were divided into 4 groups: group I, control; group II, flax seed diet (7.5 g/kg daily, orally); group III, 1% cholesterol diet; and group IV, same as group III but received flax seed (7.5 g/kg daily, orally). Blood samples were collected before and after 4 and 8 weeks on their respective diets for biochemical measurements and aortae were removed at the end of 8 weeks for estimation of atherosclerotic changes. The high cholesterol diet increased the serum level of total cholesterol (TC) and PMNL-CL without altering the levels of serum triglycerides (TG). These changes were associated with a marked development of atherosclerosis in the aorta. Flax seed reduced the development of aortic atherosclerosis by 46% and reduced the PMNL-CL without significantly lowering the serum cholesterol. Flax seed in normocholesterolemic rabbits increased serum total cholesterol and decreased PMNL-CL without significantly affecting the serum TG. Modest dietary flax seed supplementation is effective in reducing hypercholesterolemic atherosclerosis markedly without lowering serum cholesterol. Its effectiveness against hypercholesterolemic atherosclerosis could be due to suppression of enhanced production of OFRs by PMNLs in hypercholesterolemia. Dietary flax seed supplementation could, therefore, prevent hypercholesterolemia-related heart attack and strokes.
Atherosclerosis 1997 Jul 11
PMID:Dietary flax seed in prevention of hypercholesterolemic atherosclerosis. 924 61

Hyaluronan (HA) and HA-binding proteins have been implicated in a diverse array of biological processes, including development, tissue repair, and tumor invasion. However, the role of HA and HA-binding proteins in atherosclerosis and restenosis is poorly understood. PS4 (TSG-6) is a HA-binding protein expressed by cultured vascular smooth muscle cells (SMCs) in response to serum and growth factor stimulation. To delineate a possible role for TSG-6 in vascular disease progression, we have characterized its expression in cultured SMCs and in a rat vascular injury model, and we have studied the effect of constitutive overexpression of TSG-6 on SMC behavior. We found that interleukin-1 (IL-1) but not tumor necrosis factor or interleukin-6 was able to stimulate TSG-6 expression in SMCs. The IL-1 pathway could be distinguished from the growth factor pathway by its insensitivity to protein synthesis inhibitors. Furthermore, epidermal growth factor, fibroblast growth factor-1, and transforming growth factor-beta1 were all capable of augmenting maximum IL-1-induced expression of TSG-6. To gain further insight into the function of TSG-6 in SMCs, we examined the effect of constitutive overexpression of TSG-6 on these cells. We found that TSG-6-overexpressing cells grew >50% faster than control cells. Furthermore, this growth advantage became more evident in the absence of serum growth factors, with an average increase in cell number of 118% over control cells after 6 days. Consistent with these in vitro data, we observed intense immunostaining for TSG-6 in proliferating SMCs in the rat neointima after injury, whereas only an occasional cell was positive for TSG-6 in the medial layer and in nonballooned arteries. We conclude that the expression of TSG-6 is tightly controlled by growth factors and cytokines via two distinct pathways in SMCs and that overexpression of TSG-6 confers a growth advantage to these cells.
 ...
PMID:Growth factor and cytokine-regulated hyaluronan-binding protein TSG-6 is localized to the injury-induced rat neointima and confers enhanced growth in vascular smooth muscle cells. 928 29

Nuclear factor-kappa B (NF-kappa B)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-kappa B in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-kappa B system in human THP-1 monocytic cells as well as adherent monocytes. Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-kappa B dimers and induced the expression of the target gene IL-8. This activation of NF-kappa B was inhibited by the antioxidant and H2O2 scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF-kappa B activation was accompanied by an initial depletion of I kappa B-alpha followed by a slight transient increase in the level of this inhibitor protein. In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of I kappa B-alpha, accompanied by an inhibition of both NF-kappa B activation and the expression of tumor necrosis factor-alpha and interleukin-1 beta genes. These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-kappa B/Rel is likely to play an important role in atherogenesis.
 ...
PMID:Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein. 935 52

Clinical data suggest a link between the activation of the renin-angiotensin system and cardiovascular ischemic events. Leukocyte accumulation in the vessel wall is a hallmark of early atherosclerosis and plaque progression. E-Selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) are adhesion molecules participating in mediating interactions between leukocytes and endothelial cells and have been found to be expressed in athero-sclerotic plaques. We investigated whether angiotensin II, the effector of the renin-angiotensin system, influences the endothelial expression of E-selectin, VCAM-1, and ICAM-1. In coronary endothelial cells derived from explanted human hearts, angiotensin II (10(-11) to 10(-5) mol/L) induced a concentration-dependent increase in E-selectin expression. The effect was measured by cell ELISA and duplex reverse-transcription polymerase chain reaction (RT-PCR) and reached its maximum at 10(-7) mol/L. Angiotensin II induced only a small increase in E-selectin expression in cardiac microvascular endothelial cells. VCAM-1 and ICAM-1 were not affected by angiotensin II stimulation. In addition, the effect of angiotensin II-induced E-selectin expression on leukocyte adhesion was quantified under flow conditions. Angiotensin II (10(-7) mol/L) increased leukocyte adhesion significantly to 67% of the maximal effect by tumor necrosis factor-alpha at a wall shear stress of 2 dyne/cm2. This adhesion was found to be E-selectin dependent, as demonstrated by blocking antibodies. The AT1-receptor antagonist DUP 753 significantly reduced E-selectin-dependent adhesion, whereas the AT2-receptor antagonist PD 123177 had no inhibitory effect. In addition, only AT1-receptor, but not AT2-receptor, mRNA could be detected by RT-PCR in coronary endothelial cells. Therefore, it is suggested that AT1 receptors mediate the effects of angiotensin II on E-selectin expression and leukocyte adhesion on coronary endothelial cells.
 ...
PMID:Angiotensin II-induced leukocyte adhesion on human coronary endothelial cells is mediated by E-selectin. 935 54

In patients with diabetic renal failure, attention must be paid to the prevention of atherosclerosis as well as the preservation of renal function. Insulin resistance is one of the important risk-factors of atherosclerosis and the involvement of tumor necrosis factor-alpha (TNF-alpha) has been shown in the pathogenesis of insulin resistance in some diseases. A low-protein diet (LPD) is recommended for patients with advanced renal disease, but a large proportion of the total caloric intake is supplied from carbohydrates and fat in LPD. Therefore, we designed a study to determine: (1) the effect of TNF-alpha on insulin sensitivity, and (2) the effect of LPD on the TNF-alpha response and the risk factors of atherosclerosis, such as insulin sensitivity and lipid metabolism, in patients with diabetic renal failure. Insulin sensitivity was measured by an euglycemic hyperinsulinemic clamp technique and serum TNF-alpha level and in vitro release of TNF-alpha from peripheral blood mononuclear cells (PBMCs) was measured in patients with diabetic renal failure. A significant negative correlation was observed between lipopolysaccharide-stimulated TNF-alpha release from PBMCs and insulin sensitivity (r = -0.58, p < 0.05). Secondly, risk factors of atherosclerosis were measured before and two weeks after the introduction of LPD in patients with diabetic renal failure. LPD did not have any significant effect on insulin sensitivity, the production of TNF-alpha by PBMCs, lipid metabolism and glucose metabolism. These results indicate that: (1) TNF-alpha derived from PBMCs might affect insulin sensitivity in patients with diabetic renal failure, and (2) LPD does not have any significant effect on the risk factors of atherosclerosis.
 ...
PMID:[Role of tumor necrosis factor-alpha in insulin sensitivity and effect of low protein diet on the TNF-alpha response in patients with diabetic renal failure]. 939 42

The induction of monocyte chemoattractant protein-1 (MCP-1) in vascular endothelial cells is thought to be an initial event in the development of atherosclerotic lesions. Therefore, inhibition of MCP-1 production may exhibit some effects in preventing atherosclerosis. In the present study, we found that 10 microM cilostazol, a cAMP phosphodiesterase inhibitor, increased the intracellular cAMP content by a twenty-five times of the basal level and resulted in the reduction of basal MCP-1 release by 41% from 168 +/- 11 ng/24 hr/mg protein to 99 +/- 14 ng/24 hr/mg protein (P < 0.001) from cultured human umbilical vein endothelial cells. Furthermore, 10 microM cilostazol also significantly attenuated the dose-dependent increment of MCP-1 production by tumor necrosis factor-alpha. The inhibition was consistent with the reduction of MCP-1 mRNA level, possibly through reduced activation of transcription factor NF-kappa B level. Similarly, 1 mM dibutyryl cAMP inhibited MCP-1 production in endothelial cells. These data suggest that cilostazol inhibits MCP-1 production through increased intracellular cAMP levels and modulation of its expression in vascular endothelial cells.
 ...
PMID:Cilostazol, a cAMP phosphodiesterase inhibitor, attenuates the production of monocyte chemoattractant protein-1 in response to tumor necrosis factor-alpha in vascular endothelial cells. 940 74

During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
 ...
PMID:Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. 941 77


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>