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)

The hydrolysis of lipoprotein triglycerides is catalyzed by lipoprotein lipase (LPL), an enzyme found in many tissues. We have examined tissue LPL activity (LPLA) in rats with experimentally-induced hyperthyroidism. In younger, lighter rats, hyperthyroidism was accompanied by a decrease in LPL in adipose tissue whereas heart and diaphragm muscle LPL activities were increased. These changes are consistent with the hypothesis that the hypercatabolism and increased beta-adrenergic activity of hyperthyroidism result in characteristic changes in tissue LPLA. In older, heavier hyperthyroid animals, however, adipose tissue LPLA was increased and heart and diaphragmatic LPLA were similar to control activities. Propranolol feeding abolished the thyroxine-induced increase in adipose tissue LPLA. In euthyroid animals of similar size the response of muscle LPLA to short-term starvation was also attenuated. These changes in tissue LPLA may provide a mechanism for shunting triglyceride fatty acids away from adipose tissue for utilization by muscle in the hyperthyroid state. During growth and aging, these adaptations are modified.
Atherosclerosis 1977 Mar
PMID:Tissue lipoprotein lipase in the hyperthyroid rat. Effect of growth and aging. 84 80

Tissue antioxidant status may be compromised under conditions of dietary restriction, either as the result of a deficiency in a specific cofactor required by a particular antioxidant enzyme or of more complex alterations of a generalized nature triggered by metabolic responses to starvation. Many similarities exist between insulin-reversible abnormalities in tissue antioxidant enzyme activities seen in experimental diabetes and in animals subjected to food deprivation-induced weight loss which is associated with hypoinsulinemia. The complex alterations in tissue antioxidant enzyme activities resulting from nutritional deficiency states, disease or drug administration may have important clinical consequences. Free radical-related processes have been implicated in the pathology of certain conditions in which weight loss is frequently recommended (e.g., diabetes and atherosclerosis). It will be important to investigate the possible adverse effects of this intervention on the underlying disease process involved. Glutathione-dependent hepatic detoxification processes are impaired under conditions of nutritional deficiency. This finding not only has important clinical implications but the standard practice of fasting small laboratory animals overnight to ensure reliable drug absorption can markedly influence the results of pharmacological/toxicological experiments. Further studies of the influence of nutritional status on free radical-related processes are likely to yield valuable information which may be applicable to a variety of research and clinical problems.
 ...
PMID:Nutritional deficiency, starvation, and tissue antioxidant status. 307 49

Male rats were fed a selenium-deficient Torula yeast diet with or without 0.2 ppm selenium (as sodium selenite) in the drinking water. Selenium deficiency caused a significant increase of urinary acetoacetate excretion in fed rats, and 24 or 48 hours of starvation enhanced this effect. Two days of selenium supplementation decreased the amount of urinary acetoacetate and 3-hydroxybutyrate to 50% of the deficiency value, indicating an enzymatic impairment in the selenium-deficient rat. No selenium-dependent effect was found for the following: (1) urinary pH, amount of nitrite, glucose (negative), hemoglobin or protein, and the urine was negative for phenylketones; (2) blood content of glucose, acetoacetate, or 3-hydroxybutyrate; or (3) liver content of glycogen, glucose, acetoacetate, or 3-hydroxybutyrate. On the other hand, the liver content of triglycerides was significantly lower in selenium deficiency. Indications for a higher content of ketone bodies (acetoacetate plus 3-hydroxybutyrate) in the kidneys from selenium-deficient rats were found. The increased urinary excretion of ketone bodies on selenium deficiency may indicate an impairment of lipid and ketone body turnover (in the kidney), or a decreased kidney reabsorption rate. Possible implications of these results in connection with protective roles of selenium in atherosclerosis and carcinogenesis are suggested.
 ...
PMID:Impaired ketone body metabolism in the selenium deficient rat. Possible implications. 405 13

Low dehydroepiandrosterone (DHEA) and hyperinsulinaemia are assumed to be risk factors of atherosclerosis. Exogenous hyperinsulinaemia during hyperinsulinaemic clamp decreases DHEA. We have evaluated interaction of these hormones during 2 weeks of therapeutic starvation in 11 obese patients (mean BMI 41.2 kg/m2), 5 nondiabetics and 6 diabetics with diet only therapy. Comparing diabetics with normals we have found no differences in BMI and blood DHEA, DHEAS and insulin levels. We have found a light implication of negative correlation of insulin to DHEA and DHEAS level in diabetics (r = -0.71, -0.73, p = 0.16, 0.18). During starvation insulinaemia is declining, DHEA initial increase is followed by a decrease (r = 0.93, p = 0.01). We conclude that insulin decrease during starvation could be a cause of DHEA decrease. This finding is unexpected according to the potential of exogenous insulin to suppress DHEA. Further investigation of endogenous DHEA and insulin relation is necessary.
 ...
PMID:Dehydroepiandrosterone and insulinaemia. 871 73

1. Methylglyoxal is a reactive alpha-oxoaldehyde and physiological metabolite formed by the fragmentation of triose-phosphates, and by the metabolism of acetone and aminoacetone. 2. Methylglyoxal modifies guanylate residues to form 6,7-dihydro-6,7-dihydroxy-6-methyl-imidazo[2,3-b]purine-9(8)one and N2-(1-carboxyethyl)guanylate residues and induces apoptosis. 3. Methylglyoxal modifies arginine residues in proteins to form N(delta)-(4,5-dihydroxy-4-methylimidazolidin-2-yl) ornithine, N(delta)-(5-hydro-5-methylimidazol-4-on-2-yl)ornithine and N(delta)-(5)methylimidazol-4-on-2-yl)ornithine residues. 4. Methylglyoxal-modified proteins undergo receptor-mediated endocytosis and lysosomal degradation in monocytes and macrophages, and induce cytokine synthesis and secretion. 5. Methylglyoxal is detoxified by the glyoxalase system. Decreased detoxification of methylglyoxal may be induced pharmacologically by glyoxalase I inhibitors which have anti-tumor and anti-malarial activities. 6. The modification of nucleic acids and protein by methylglyoxal is a signal for their degradation and may have a role in the development of diabetic complications, atherosclerosis, the immune response in starvation, aging and oxidative stress.
 ...
PMID:Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification--a role in pathogenesis and antiproliferative chemotherapy. 885 85

1. In the present study we examined the effects of PCA-4230, a novel antithrombotic agent, on the growth of cultured A10 vascular smooth muscle cells (rat'aorta). 2. The action of PCA-4230 on cell proliferation and on serum-induced DNA synthesis was determined by measuring the cell number and the incorporation of the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU), respectively. 3. PCA-4230 reversibly inhibited vascular smooth muscle cell proliferation. The increase in cell number was significantly reduced in the presence of 1 and 50 microM PCA-4230. 4. DNA synthesis was concentration-dependently inhibited by PCA-4230 (0.5 to 50 microM) in A10 cells that were synchronized by 48 h serum starvation and then re-stimulated by serum repletion, with an IC50 value of 13 microM. However, serum-induced DNA synthesis in bovine aortic endothelial cells was not significantly affected by PCA-4230. In addition, PCA-4230 (50 microM) caused a significant drop in PDGF-BB-mediated BrdU incorporation in A10 cells. 5. The effect of PCA-4230 on serum-induced DNA synthesis was compared to that elicited by nifedipine, another dihydropyridine-class inhibitor of vascular smooth muscle proliferation. PCA-4230 (10 microM) elicited a degree of inhibition similar to that of nifedipine at equimolar concentration. 6. To define the nature of the cell proliferation inhibition, an evaluation of cell cycle progression was undertaken. Flow cytometry studies of DNA content in synchronized cells revealed a block of the serum-inducible cell cycle progression. This inhibitory effect was markedly reduced when PCA-4230 was added 2 h after serum repletion. 7. Accordingly, PCA-4230 (50 microM) caused a 95 and 90% decrease in the elevation of c-fos and c-jun proto-oncogenes expression as evaluated by Northern blot analysis of mRNA induced early after serum addition. 8. The present results indicate that PCA-4230 inhibits vascular smooth muscle cell proliferation, in culture, by altering the cell cycle progression. Flow cytometric studies of DNA content and the down regulation of c-fos and c-jun proto-oncogenes, suggest that the drug is acting at the early G0/G1 transition phase. PCA-4230 may hold promising potential for the prevention of structural abnormalities of blood vessels associated with atherosclerosis and vascular diseases.
 ...
PMID:Antiproliferative effects of PCA-4230, a new antithrombotic drug, in vascular smooth muscle cells. 910 13

Most previous researches on neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) have focused on the nervous system, because their receptors are widely distributed in neuronal tissues. Recently, however, the participation of neurotrophins in inflammation and atherosclerosis has been proposed. Therefore, the gene expression of neurotrophins is now an urgent issue is to be investigated in nonneuronal tissues. Here, we evaluated the gene expression of neurotrophins and their receptors in rat cultured vascular smooth muscle cells (VSMCs) by the reverse transcriptase-polymerase chain reaction method. The transcripts of NGF, NT-3, and TrkC (high-affinity receptor for NT-3), and two BDNF alternative spliced transcript variants with exons 3 and 4 were clearly detected in VSMCs cultured under conventional culture conditions. The upregulation of mRNA levels for NGF, two BDNF variants with exons 1 and 2, low-affinity neurotrophin receptor, and high-affinity receptors, TrkA (for NGF) and TrkB (for BDNF), was observed in response to the treatment with serum and phorbol-ester following the serum-starvation. In contrast, the expression of NT-3 and TrkC genes was downregulated under these conditions. Co-expression of these factors and their receptors and the characteristic regulation of their gene transcriptions suggest that these factors play crucial roles in the function of VSMCs through an autocrine mechanism.
 ...
PMID:Gene expression of neurotrophins and their receptors in cultured rat vascular smooth muscle cells. 953 23

Induction of cyclin-dependent kinase inhibitor p21(Waf1/Cip1/Sdi1) triggers cell growth arrest associated with senescence and damage response. Overexpression of p21 from an inducible promoter in a human cell line induces growth arrest and phenotypic features of senescence. cDNA array hybridization showed that p21 expression selectively inhibits a set of genes involved in mitosis, DNA replication, segregation, and repair. The kinetics of inhibition of these genes on p21 induction parallels the onset of growth arrest, and their reexpression on release from p21 precedes the reentry of cells into cell cycle, indicating that inhibition of cell-cycle progression genes is a mechanism of p21-induced growth arrest. p21 also up-regulates multiple genes that have been associated with senescence or implicated in age-related diseases, including atherosclerosis, Alzheimer's disease, amyloidosis, and arthritis. Most of the tested p21-induced genes were not activated in cells that had been growth arrested by serum starvation, but some genes were induced in both forms of growth arrest. Several p21-induced genes encode secreted proteins with paracrine effects on cell growth and apoptosis. In agreement with the overexpression of such proteins, conditioned media from p21-induced cells were found to have antiapoptotic and mitogenic activity. These results suggest that the effects of p21 induction on gene expression in senescent cells may contribute to the pathogenesis of cancer and age-related diseases.
 ...
PMID:Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. 1076 Feb 95

Abnormal proliferation of vascular smooth muscle cells (VSMCs) is an important feature of atherosclerosis, restenosis, and hypertension. Although multiple mediators of VSMC growth have been identified, few effective pharmacological tools have been developed to limit such growth. Recent evidence indicating an important role for oxidative stress in cell growth led us to investigate the potential role of aldose reductase (AR) in the proliferation of VSMCs. Because AR catalyzes the reduction of mitogenic aldehydes derived from lipid peroxidation, we hypothesized that it might be a potential regulator of redox changes that accompany VSMC growth. Herein we report several lines of evidence suggesting that AR facilitates/mediates VSMC growth. Stimulation of human aortic SMCs in culture with mitogenic concentrations of serum, thrombin, basic fibroblast growth factor, and the lipid peroxidation product 4-hydroxy-trans-2-nonenal (HNE) led to a 2- to 4-fold increase in the steady-state levels of AR mRNA, a 4- to 7-fold increase in AR protein, and a 2- to 3-fold increase in its catalytic activity. Inhibition of the enzyme by sorbinil or tolrestat diminished mitogen-induced DNA synthesis and cell proliferation. In parallel experiments, the extent of reduction of the glutathione conjugate of HNE to glutathionyl-1,4-dihydroxynonene in HNE-exposed VSMCs was decreased by serum starvation or sorbinil. Immunohistochemical staining of cross sections from balloon-injured rat carotid arteries showed increased expression of AR protein associated with the neointima. The media of injured or uninjured arteries demonstrated no significant staining. Compared with untreated animals, rats fed sorbinil (40 mg. kg(-1). d(-1)) displayed a 51% and a 58% reduction in the ratio of neointima to the media at 10 and 21 days, respectively, after balloon injury. Taken together, these findings suggest that AR is upregulated during growth and that this upregulation facilitates growth by enhancing the metabolism of secondary products of reactive oxygen species.
 ...
PMID:Involvement of aldose reductase in vascular smooth muscle cell growth and lesion formation after arterial injury. 1089 12

Apolipoprotein AI (apoAI) expression is inversely related to the incidence of atherosclerosis. ApoAI expression is also influenced by the nutritional state and diabetes. We used both cell culture and animal models to examine the effect of fasting and ketoacidosis on apoAI gene expression. Two days of food deprivation in rats increased hepatic and intestinal apoAI mRNA by 2.6- and 2.3-fold, respectively (P < .05). The absolute concentration of plasma apoAI did not change. However, the plasma apoAI concentration relative to the plasma concentration of serum proteins was increased 23% (P < .05). In fasting rats, there was a significant positive correlation between the serum beta-hydroxybutyrate concentration and hepatic or intestinal apoAI mRNA level. Despite this correlation, changes in apoAI mRNA are probably not mediated by ketone bodies, since neither hepatic nor intestinal apoAI mRNA levels were altered in rats maintained on a ketogenic diet for 10 days or treated with isobutyramide, an orally active ketone analog. In addition, the activity of the rat apoAI promoter was not altered in Hep G2 cells treated with isobutyramide or fatty acids or exposed to hypoglycemic conditions, while dexamethasone increased promoter activity 1.9-fold (P < .05). These data indicate that metabolic changes other than ketone bodies, such as an increase in plasma glucocorticoids, may account for starvation-induced expression of apoAI.
 ...
PMID:Induction of the apolipoprotein AI gene by fasting: a relationship with ketosis but not with ketone bodies. 1114 19


1 2 3 4 5 6 Next >>