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)

Oxidation and scavenger receptor-mediated uptake of low density lipoprotein (LDL) in intimal macrophages are believed to be key events in the development of atherosclerosis. We report here that oxidized LDL increases DNA synthesis, expression of HLA-DR, and interleukin-2 receptors in T cells. The stimulatory effect of oxidized LDL was not due to a direct effect on T cells but required the presence of monocytes. Oxidized LDL also stimulated the release of interleukin-1 beta from monocytes. The maximal effect of oxidized LDL on T-cell activation and interleukin-1 beta release occurred at a concentration of 1 micrograms/ml. Native LDL also had the capacity to activate T cells, although only at higher concentrations. The stimulatory effect of both native and oxidized LDL was inhibited by superoxide dismutase. Monocytes as well as T cells were found to have the ability to oxidize LDL, suggesting that the stimulatory effect of native LDL may arise as a result of LDL oxidation during incubation with monocytes and T cells. The results suggest that oxidized LDL may activate T cells in atherosclerotic lesions.
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PMID:Induction of T-cell activation by oxidized low density lipoprotein. 155 37

In cultured rat aortic smooth cells, endothelin-1 induced tyrosine phosphorylation of at least five proteins with molecular masses of about 79, 77, 73, 45 and 40 kDa in dose- and time-dependent manners. Platelet-derived growth factor also induced tyrosine phosphorylation of the same set of proteins in addition to other proteins including platelet-derived growth factor receptors. This growth factor markedly stimulated DNA synthesis and an increase in cell number in this cell type, but endothelin-1 failed to stimulate these responses under the same conditions. These results demonstrate for the first time that endothelin-1 induces tyrosine phosphorylation of some proteins but suggest that these reactions are not enough to stimulate proliferation of vascular smooth muscle cells.
Atherosclerosis 1992 Jan
PMID:Stimulation of protein-tyrosine phosphorylation by endothelin-1 in cultured vascular smooth muscle cells. 157 17

The effects of oxidized human plasma low density lipoproteins (Ox-LDL) on the proliferation of cultured aortic smooth muscle cells was studied, employing viable cell counting, [3H] thymidine incorporation into DNA, and the release of lactate dehydrogenase (LDH) into the medium. Oxidized LDL (prepared by incubation of LDL with copper sulfate) exerted a concentration-dependent stimulation (2 fold, compared to control) of aortic smooth muscle cell proliferation at low concentrations (0.1 micrograms-10 micrograms/ml medium). On the other hand, at high concentrations (25-200 micrograms/ml), Ox-LDL produced a pronounced decrease in viable cells, a decrease in the incorporation of [3H] thymidine into DNA, and an increase in the release of LDH in the medium. In this report, the previously postulated biological roles of oxidized-LDL in atherosclerosis are discussed in view of these findings.
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PMID:Role of oxidized human plasma low density lipoproteins in atherosclerosis: effects on smooth muscle cell proliferation. 158 38

Platelets and their interaction with the vessel wall play a role in atherogenesis and in the formation of the coronary thrombus. Supplementation of the diet with n-3 PUFA shifts the platelet-vessel wall interaction in anti-thrombotic direction in healthy persons and in patients with IHD. This is in part caused by an inhibition of Tx synthesis and also by an increased synthesis of PGI2 and PGI3 in the vessel wall. However, the clinical significance of these findings needs to be elucidated in clinical trials. Large, dense platelets are more reactive than small ones. Platelet size and density are determined at thrombopoiesis. Large, reactive platelets have in states with an increased platelet demand been shown to be produced from large, high-ploidy megakaryocytes. In patients with thrombopoiesis in steady-state an inverse relation between the bleeding time and both the DNA content and the size of the bone marrow megakaryocytes has been demonstrated. The bone marrow megakaryocytes in these patients were larger in men than in women, which may explain the sex difference in bleeding time observed by others. In experimental atherosclerosis changes in megakaryocyte size have been demonstrated. The significance of these changes are still unclear. In a single study stimulation of the platelet-megakaryocyte axis was associated with an acceleration of experimental atherosclerosis. This study suggests that large, high ploidy megakaryocytes may produce a large amount of atherogenic platelets that may be responsible for the increased formation of atheroma in this model. However, due to the complexity of the study design this hypothesis needs verification in other experimental and clinical studies. In patients suffering from an AMI the mean platelet volume is increased. The bleeding time is shortened at the time of infarction in these patients probably due to increased synthesis of TxA2, but an increased production of adrenaline may also be of importance. These large, reactive platelets present in AMI may be a reflection of an altered thrombopoiesis in these patients. It remains to be established whether these changes in platelet reactivity are present before the time of coronary thrombus formation.
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PMID:The platelet-vessel wall interaction in experimental atherosclerosis and ischaemic heart disease with special reference to thrombopoiesis. 161 18

Although platelet-derived growth factor (PDGF) is thought to be a major mediator of atherosclerotic disease, the pathophysiology of diabetic vasculopathy, including atherosclerosis, is unclear. By means of an enzyme immunoassay that used a monoclonal antibody against human PDGF-B chain, PDGF-like immunoreactivity was determined in serum, platelet-poor plasma, and platelet lysate of 28 patients with non-insulin-dependent diabetes mellitus and 11 control subjects. Growth-promoting activity was also measured by tritiated thymidine incorporation into DNA of cultured human fibroblasts. The PDGF-like immunoreactivity in serum was correlated (r = 0.42; p less than 0.01) with that in platelet lysate prepared from a fixed volume of blood. Furthermore, a correlation (r = 0.70; p less than 0.001) was found between the PDGF-like immunoreactivity and the growth-promoting activity in platelet lysate but not in serum. There was no significant difference between patients with diabetes and control subjects with respect to the PDGF-like immunoreactivity in serum or in platelet lysate (38.2 +/- 2.2 vs 42.8 +/- 3.1 ng/ml or 49.1 +/- 2.4 vs 56.2 +/- 3.4 ng/mg protein; mean +/- SEM). In contrast, the serum growth-promoting activity was lower (p less than 0.05) in patients with diabetes than in control subjects (88.1% +/- 7.1% vs 117.4% +/- 6.9%) and there was a negative correlation (r = -0.39; p less than 0.05) between the serum growth-promoting activity and the fasting plasma glucose level. The growth-promoting activity in platelet lysate of patients with diabetes did not differ from that of the control subjects (59.9% +/- 11.6% vs 65.9% +/- 11.2%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet-derived growth factor and growth-promoting activity in the serum samples and platelets of patients with non-insulin-dependent diabetes mellitus. 161 32

Inherited defects in the gene for the low density lipoprotein (LDL)-receptor give rise to familial hypercholesterolaemia (FH), a disorder in which defective catabolism of LDL causes a marked increase in its concentration in plasma. As a result, there is excessive deposition of cholesterol in the arterial wall leading to accelerated atherosclerosis and premature coronary heart disease in most patients, although there are differences in its severity. Many different mutations have been found in the LDL receptor genes of FH patients, and although this heterogeneity has provided information about the relationship between structure and function in different domains of the protein, it makes simple DNA-based diagnosis of the disease impossible. When sufficient groups of patients with defined mutations are available it will be possible to determine the relative importance of any particular mutation compared with other genetic or environmental factors in relation to the severity of their symptoms or their response to treatment.
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PMID:Familial hypercholesterolaemia and LDL receptor mutations. 161 86

Diabetic patients who develop proteinuria show a marked increase in cardiovascular morbidity and mortality. The precise pathogenesis of human diabetic kidney disease and the factors responsible for the susceptibility to it remain, in part, obscure. However, there is now evidence that renal disease clusters in families and that genetic factors may be of central importance in determining susceptibility. Predisposition to arterial hypertension has been suggested as playing a contributory role in the development of kidney disease. Hypertrophic processes may be implicated in the susceptibility to arterial wall damage and glomerular injury in diabetes. Interestingly, fibroblasts of patients with diabetic nephropathy show a higher Na+/H+ antiport activity and a greater 3H-thymidine incorporation into DNA than fibroblasts of diabetic patients without nephropathy. The first clinical signs of renal involvement are the appearance of microalbuminuria and a small elevation in arterial pressure. Mesangial expansion accompanies these changes. Microalbuminuria is associated with abnormalities of lipoprotein profiles and higher Na+/Li+ countertransport rates. The environmental changes brought about by diabetes could lead in susceptible individuals to increased systemic and intraglomerular pressures on the one hand and to mesangial expansion on the other. These two processes would cause proteinuria and glomerulosclerosis. Lipid abnormalities may further aggravate the renal histological damage and, in combination with hypertension, contribute to the accelerated atherosclerosis typical of patients with diabetic kidney disease. A vicious circle would thus be triggered, involving reduction in renal function, further hypertension, proteinuria, glomerular obsolence and hyperlipidaemia, and eventually end-stage renal failure or premature cardiovascular death.
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PMID:Risk factors for renal and cardiovascular disease in diabetic patients. 165 64

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a hereditary disorder with clinical manifestations including corneal opacity, premature atherosclerosis and renal failure. In this study, we analyzed the molecular base underlying a case of Japanese LCAT deficiency, in which both LCAT mass and activity of the proband were nearly absent. DNA blot hybridization analysis showed no gross rearrangement in the LCAT gene of the proband. The nucleotide sequence analysis of the cloned LCAT gene demonstrated only an extra nucleotide "C" insertion at the first exon, when compared to the sequence of wild type. This single base insertion caused a shift of the following reading frame, probably resulting in a truncated abnormal LCAT polypeptide that consist of only 16 amino acids. The direct sequence analysis of PCR-amplified DNA showed only the same insertion, indicating that the LCAT-deficient proband is a homozygote for the mutant allele. These results indicate that the clinical and biochemical feature of the patient is mainly caused by a complete deficiency of the enzyme based on a homozygous abnormality of LCAT gene.
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PMID:Molecular defect in familial lecithin:cholesterol acyltransferase (LCAT) deficiency: a single nucleotide insertion in LCAT gene causes a complete deficient type of the disease. 166 3

Oxidant injury has been implicated in the pathogenesis of inflammatory, metabolic and toxic insults, in ischemic-reperfusion injury, and in carcinogenesis, aging and atherosclerosis. Oxidant injury is initiated by free radicals and reactive oxygen molecules which are generated by activated neutrophils, monocytes, and mesangial cells, during normal and abnormal metabolic processes, and from the metabolism of exogenous drugs and toxins. When cells and organs are exposed to oxidant stress, several different antioxidant defense mechanisms operate to prevent or limit oxidant injury. When antioxidant defense mechanisms are decreased, or when the generation of reactive oxygen molecules is increased, oxidant injury results from the shift in the oxidant/antioxidant balance. Oxidant-induced alterations of proteins, membranes, DNA, and basement membranes leads to cell and organ dysfunction. Several renal diseases including glomerulonephritis, vasculitis, toxic nephropathies, pyelonephritis, acute renal failure, and others are likely to be mediated at least in part by oxidant injury. In the future, mechanisms to decrease the generation of reactive oxygen molecules and/or antioxidant therapy may develop into new avenues of therapeutic intervention.
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PMID:Reactive oxygen molecules, oxidant injury and renal disease. 166 82

Absent hepatic lipase (HL) activity results in dyslipidemia and premature atherosclerosis. DNA sequencing of the HL gene from subjects with heritable HL deficiency identified a new C to T substitution within exon 8 that in the mature enzyme caused a threonine to methionine change at position 383 (T383M). With a rapid DNA detection method we observed that all 6 individuals with complete HL deficiency from 2 families had the T383M mutation. None of 50 random unrelated unaffected subjects had this mutation. We propose that T383M is specific to families with heritable HL deficiency. Furthermore, structural variation at the HL gene, possibly in combination with other factors, appears to be etiologic in HL deficiency.
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PMID:A hepatic lipase gene mutation associated with heritable lipolytic deficiency. 167 86


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