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 effect of nicotinic acid was investigated in Rhesus monkeys. Subcutaneous injections of nicotinic acid lower the plasma very low density lipoprotein (VVLDL) and low density lipoprotein (HDL) concentration. The fall in LDL concentration is not accompained by any change in the lipid or protein composition of either lipoprotein. Analysis by Sephadex gel chromatography and polyacrylamide-gel electrophoresis showed that the proteins of monkey VLDL and LDL are qualitatively similar to those of human VLDL and LDL, although there are differences in the proportions of the various proteins present in the two species. Subcutaneous injections of nicotinic acid diminish the maximum incorporation of 14C from [14C]threonine into VLDL and LDL apoproteins, but have no effect on incorporation into albumin or HDL apoprotein. Peak incorporations into the apo-B and apo-C of VLDL are diminished to about equal extents by nicotinic acid. Comparison of the amount of 14C lost from apo-B of VLDL after the peak of incorporation, with that gained by apo-B of LDL during the same period, suggests that some of the circulating apo-B of LDL IS DERIVED FROM SOURCES OTHER THAN CIRCULATING VLDL.
Atherosclerosis
PMID:The effect of nicotinic acid on the metabolism of the plasma lipoproteins of rhesus monkeys. 16 24

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

Elastin preparations from intimal layers and the media of normal and atherosclerotic human aortae were analyzed for protein and lipid content. In atherosclerotic aortae, elastin from plaques was compared with elastin from adjacent normal appearing areas of the same aorta. Arterial elastin purified by alkaline extraction appeared to be a protein-lipid complex containing free and ester cholesterol, phospholipids, and triglycerides. The lipid component of normal arterial elastin was small (1-2%). With increasing severity of atherosclerosis, there was a progressive accumulation of lipid in intimal elastin from plaques, reaching a mean lipid content of 37% in severe plaques. The increase in the lipid content of plaque elastic preparations was mainly due to large increases in cholesterol, over 80% of which was cholesteryl ester. This deposition of cholesterol in plaque elastin accounted for 20-34% of the total cholesterol content of the plaque. The increased lipid deposition in plaque elastin was associated with alterations in the amino acid composition of plaque elastin. In elastin from plaque intima, the following polar amino acids were increased significantly: aspartic acid, threonine, serine, glutamic acid, lysine, histidine, and arginine; whereas, cross-linking amino acids: desmosine, isodesmosine, and lysinonorleucine were decreased significantly. The amino acid and lipid composition of elastin from normal appearing aortic areas was comparable to that of normal arterial elastin except for intimal elastin directly adjacent to and medial elastin directly below the most severe plaques.The data indicate that the focal lipid deposition in early atherosclerotic plaques is due to a large extent to lipid accumulations in altered elastin protein of localized intimal areas. Continued lipid deposition in altered elastin appears to contribute substantially to the progressive lipid accumulation in the plaque. The study suggests that elastin of intimal elastic membranes may play an important role in the pathogenesis and progression of atherosclerosis.
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PMID:The protein and lipid composition of arterial elastin and its relationship to lipid accumulation in the atherosclerotic plaque. 509 73

Increased generation of active oxygen species such as H2O2 and O2- may be important in vascular smooth muscle cell growth associated with atherosclerosis and restenosis. In previous work, we showed that H2O2 stimulated vascular smooth muscle cell growth and proto-oncogene expression. In the present study, we compared the effects of H2O2 and O2- on cultured rat aortic vascular smooth muscle cell growth and signal transduction. O2- was generated in a concentration-dependent manner by the naphthoquinolinedione LY83583. Vascular smooth muscle cell growth, as measured by [3H]thymidine incorporation, was stimulated by 200 mumol/L H2O2 (110% increase versus 0.1% serum) and 1 mumol/L LY83583 (175% increase) to levels comparable to 10 ng/mL platelet-derived growth factor (210% increase). Since activation of mitogen-activated protein kinase (MAP kinase) is one of the earliest growth factor signal events, the activity of MAP kinase was measured by changes in mobility on Western blot and by phosphorylation of myelin basic protein. There was a concentration-dependent increase in MAP kinase activity by LY83583 (maximum, 10 mumol/L) but not by H2O2. The time course for activation of MAP kinase by LY83583 showed a maximum at 5 to 10 minutes with return to baseline by 20 minutes. Activation of MAP kinase by LY83583 was protein kinase C dependent. Expression of MAP kinase phosphatase-1 (MKP-1), a transcriptionally regulated redox-sensitive protein tyrosine/threonine phosphatase, was also measured. Although H2O2 induced MKP-1 mRNA to a greater extent than did LY83583, the increased MKP-1 expression could not explain the inability of H2O2 to stimulate MAP kinase, because mRNA levels were not detected until 60 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential activation of mitogen-activated protein kinases by H2O2 and O2- in vascular smooth muscle cells. 754 May 16

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive sterol storage disease characterized by the accumulation of a bile alcohol, cholestanol, in diverse tissues. The disorder is manifested by extensive nervous system involvement, juvenile cataracts, tendon xanthomas, and premature atherosclerosis and is caused by sterol 27-hydroxylase (EC 1.14.13.15) mutations. Recently, two mutations were shown to cause CTX in four Jewish families of Moroccan origin. An additional mutant allele, found in a Jewish family of Algerian origin is characterized here. Sequence analysis revealed a C to T transition at cDNA position 1037 which predicted a threonine to methionine substitution at residue 306 (designated T306M). It is highly suggestive, but not definitive, that this transition is the mutation causing CTX in this family. A search for additional cases from Jewish families of North African extraction identified five new families including 10 cases. The three sterol 27-hydroxylase gene mutations account for all 10 CTX families and their presence may suggest the existence of positive selective forces that lead to an increased prevalence of this relatively rare disease in Jews from North Africa.
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PMID:Molecular genetics of cerebrotendinous xanthomatosis in Jews of north African origin. 801 82

Elevated levels of lipoprotein(a) (Lp(a)) have been strongly correlated with the development of atherosclerosis in human populations. Lp(a) is distinguishable from low density lipoprotein by the presence of the unique protein component apolipoprotein(a) (apo(a)), which contains repeated domains that closely resemble that of plasminogen kringle IV. Using human embryonic kidney cells, we have expressed a recombinant form of apo(a) (r-apo(a)) containing 17 kringle IV-like domains. We have utilized this recombinant expression system to study the assembly of Lp(a) particles. We have demonstrated that Lp(a) particles containing r-apo(a) can be assembled extracellularly in plasma by covalent linkage to low density lipoprotein. Using site-directed mutagenesis, we have demonstrated that a cysteine residue present at position 4057 of the apo(a) protein (i.e., in the penultimate kringle IV repeat) mediates this covalent linkage. Using polymerase chain reaction amplification of liver apo(a) complementary DNA, we have demonstrated the presence of a polymorphism in apo(a) kringle IV type 10, which results in the substitution of a threonine for a methionine. Preliminary studies indicate that the presence of a threonine at this position may enhance the interaction of Lp(a) with lysine-Sepharose.
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PMID:Analysis of structure--function relationships in human apolipoprotein(a). 806 77

Individuals with hepatic lipase (HL) deficiency are often characterized by elevated levels of triglycerides and cholesterol and may be subject to premature atherosclerosis. Missense mutations in the HL gene have been identified in two affected families: substitutions of serine for phenylalanine at amino acid 267 and threonine for methionine at amino acid 383 (S267F and T383M, respectively). To confirm the role of S267F and T383M, respectively). To confirm the role of mutations separately into human HL cDNA by site-directed mutagenesis, and the resulting constructs were independently expressed in COS cells. HL activity and mass were measured and compared with wild-type HL transfectants to determine the effect of these mutations on lipase activity and secretion. Although similar amounts of HL protein were detected intracellularly after transfection with the wild-type and mutant constructs, S267F and T383M HL activity levels were markedly decreased: in S267F, no HL activity was detected, and activity levels in T383M were 38% of wild-type HL. Heparin-induced secretion of the two HL mutants was also severely affected: no detectable activity could be measured in the media of S267F, although some inactive mass (12% of wild-type HL) was secreted; mutant T383M secreted 4% and 20% of wild-type activity and mass, respectively. These results indicate that the single amino acid substitution present in HL S267F is sufficient to render the enzyme completely nonfunctional; in contrast, the T383M mutant retains partial activity but is poorly secreted. Thus, these defects appear capable of accounting for the HL-deficient phenotypes exhibited by individuals carrying the T383M and S267F mutations.
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PMID:Molecular characterization of human hepatic lipase deficiency. In vitro expression of two naturally occurring mutations. 812 42

Genetic influences in cerebrovascular disease (CVD) may act either independently or by predisposing to, or modulating, the effect of risk factors such as hypertension. Factors involved in the pathogenesis of atherosclerosis, thrombosis and vasoconstriction are important in CVD. The angiotensinogen gene has recently been linked with essential hypertension in affected sibships and a particular polymorphism in exon 2 of the angiotensinogen gene, a threonine to methionine substitution at position 235 (M235T), has been associated with pre-eclampsia and hypertension. In this study we examined the relation of M235T polymorphism to cerebrovascular disease and carotid atheroma in 100 consecutive Caucasian patients with internal carotid artery territory ischaemia (TIA or stroke), presenting to a carotid ultrasound service. Forty five age-matched controls (mostly patients' spouses) were also studied. Hypertension was defined as current treatment with anti-hypertensive agents, or SBP > 160 mm Hg or DBP > 95 mm Hg. Twelve of 100 cases (12%) and eight of 45 controls (12%) were homozygous for the T235 allele. T:M allele ratios were 0.34:0.66 in cases and 0.34:0.66 in controls. There was no relation between the polymorphism and either internal carotid stenosis or common carotid artery intima-media thickness. In the cases, mean percentage internal carotid artery stenosis was TT 18.3 (SD 18.7)%, MT 38.0 (27.1)% and MM 36.8 (30.2)%. Mean intima-media thickness was TT 0.87 (0.18) mm, MT 0.95 (0.34) mm and MM 0.88 (0.23) mm. There was no relation between the polymorphism and hypertension (TT 11 of 100 cases, six of 45 controls).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of association between angiotensinogen polymorphism (M235T) and cerebrovascular disease and carotid atheroma. 852 90

1. Transforming growth factors-beta (TGF-beta) are multifunctional proteins that regulate cell growth, differentiation, migration and extracellular matrix production and have an important role in embryonic development and tissue remodelling. 2. The diverse biological actions of TGF-beta are elicited following their interaction with type I and type II TGF-beta receptors, both of which are transmembrane serine/threonine kinases, suggesting an important role for protein phosphorylation in the mechanism of action of these cytokines on the growth of cells and their extracellular environment. 3. Alterations in TGF-beta gene expression and action in various cell types associated with the cardiovascular system may contribute to the pathophysiology of a number of diseases, such as hypertension, atherosclerosis and restenosis, as well as the development of cardiac abnormalities.
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PMID:Regulation and interactions of transforming growth factor-beta with cardiovascular cells: implications for development and disease. 893 7

Vascular smooth muscle cell (SMC) proliferation is a key event in the development of (spontaneous) atherosclerosis, hypertension-related arteriosclerosis, angioplasty-induced restenosis and venous bypass graft arteriosclerosis. Many factors or environmental stimuli are believed to be responsible for SMC growth or hypertrophy in the vessel wall. How these environmental stimuli or signals applied onto the surface of SMCs are transduced into the cell nucleus resulting in quantitative and qualitative changes in gene expression in SMCs of arterial walls is largely unknown. Mitogen-activated protein (MAP) kinases are rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in transmitting transmembrane signals required for cell growth and differentiation. Recent studies have focused on the signalling events in vascular tissues in vivo and in cultured SMCs in vitro. It has been demonstrated that acute hypertension and angioplasty rapidly induced MAP kinase activation in the arterial wall. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. A similar MAP kinase activation can be mimicked in in vitro cultured SMCs stimulated by either shear stress or cyclic strain stretch, suggesting direct effects of mechanical force. Interestingly, physical forces rapidly resulted in phosphorylation of platelet-derived growth factor (PDGF) receptor, an activated state, in cultured SMCs. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signalling pathways usually used by growth factors. These findings have significantly enhanced our knowledge concerning the pathogenesis of arteriosclerosis and provide a basis for therapeutic intervention on vascular diseases.
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PMID:Signal transduction in arteriosclerosis: mechanical stress-activated MAP kinases in vascular smooth muscle cells (review). 985 3


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