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)

We have isolated from a rabbit liver cDNA library, clones coding for the 66-kDa glycoprotein (GP66) characterized previously by EMR1a/212D monoclonal antibody (Nakagami, K., Shimasaki, O., Sato, R., Komine, Y., Ohkuma, S. and Takano, T. (1989) Am. J. Pathol. 135, 93-100), which recognizes the extracellular regions of atherosclerotic arterial wall. The clone spans the sequence coding for the entire GP66 (456 amino acids) and 19 amino acids of signal peptide. GP66 deduced from nucleotide sequence contained an Arg-Gly-Asp cell attachment sequence and had a 76% amino acid sequence homology with human vitronectin. Furthermore, EMR1a/212D recognized rabbit vitronectin purified by heparin-affinity chromatography. RNA blot hybridization detected one transcript of the same size in normal and Watanabe-heritable hyperlipidemic rabbit liver. The levels of plasma GP66 and liver GP66 mRNA were not altered, whereas 9-fold greater accumulation of GP66 was observed in thoracic aorta of Watanabe-heritable hyperlipidemic rabbit. These results suggest that GP66 is rabbit vitronectin and that it is vitronectin which selectively accumulates in thoracic aorta with the development of atherosclerosis.
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PMID:Monoclonal antibody EMR1a/212D recognizing site of deposition of extracellular lipid in atherosclerosis. Isolation and characterization of a cDNA clone for the antigen. 170 Nov 77

The endothelial cells can release both relaxing and contracting substances. The former include prostacyclin and endothelium-derived relaxing factor (EDRF, which most likely is nitric oxide, or a nitrosoderivative releasing nitric oxide, derived from L-arginine). Candidates as endothelium-derived contracting factors (EDCF) include superoxide anions thromboxane A2 and the peptide endothelin. Endothelium-derived relaxing factor causes relaxation of vascular smooth muscle by activation of the soluble form of guanylate cyclase which leads to an accumulation of cyclic GMP; it also reduces platelet adhesion and aggregation. The latter effect is synergistic with the inhibition evoked by prostacyclin. The release of EDRF and prostacyclin plays a key role in the protective role of the endothelium against vasospasm and the unwanted coagulation of blood. Indeed, thrombin and aggregating platelets are potent stimuli for the release of EDRF. The platelet-products responsible are the adenine nucleotides, ADP and ATP, which activate P2y-purinergic receptors on the endothelial cells and 5-hydroxytryptamine (serotonin) that stimulates 5-HT1-like serotonergic receptors. The response to serotonin, but not that to the adenine nucleotides, is mediated by a pertussis toxin-sensitive mechanism. When endothelial cells regenerate, or are cultured, they selectively lose the pertussis toxin-sensitive mechanism of release, which results in a marked decrease in sensitivity to exogenous and platelet-released serotonin. As a consequence, the endothelial cells exhibit a considerably reduced response to aggregating platelets. This phenomenon, which can be exacerbated by hypercholesterolemia, favors ongoing platelet aggregation and vasospasm, and constitutes a first step toward atherosclerosis.
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PMID:Platelet-derived serotonin, the endothelium, and cardiovascular disease. 171 75

Endothelial cells contain an enzyme(s) which produces nitric oxide from L-arginine in response to a variety of mechanical stimuli as well as to autacoids and local and circulating hormones. Nitric oxide is a potent vasodilator and inhibitor of platelet function; it exerts its effects via activation of soluble guanylate cyclase and subsequent formation of cyclic 3'-5'-guanosine monophosphate. In the kidney, activation of the endothelial L-arginine pathway is associated with increases in renal blood flow, diuresis and natriuresis, while the glomerular filtration rate remains constant. The activity of the endothelial L-arginine pathway is impaired in hypertension and during chronic therapy with cyclosporine A. In addition, diabetes and atherosclerosis impair this pathway. Thus, the endothelial L-arginine pathway plays an important role in the local regulation of blood flow. Alterations in the activity of this pathway may play an important role in the pathophysiology of hypertension and renal disease.
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PMID:The endothelial L-arginine/nitric oxide pathway and the renal circulation. 175 83

Platelet activity in circulating blood is controlled by platelet-vessel-wall interactions. This includes the generation of endothelium-derived factors, such as the arachidonic acid metabolite prostacyclin and endothelium-derived relaxing factor (EDRF), probably NO, generated from L-arginine. Both compounds inhibit platelet function and are arterial vasodilators. Endothelial dysfunction, e.g. during advanced atherosclerosis, is associated with reduced local formation of these compounds. This may result in platelet hyperreactivity and an increased risk of acute thrombembolic complications. Exogenous administration of synthetic PGI2-mimetics inhibits platelet function. This is a short-term action and the dosage is limited by systemic hypotension. NO-donators (molsidomine, organic nitrates) inhibit platelet-related vasospasm in stenosed coronary arteries in animal experiments. The significance of antiplatelet effects of organic nitrate vasodilators regarding their antianginal effectivity requires further study.
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PMID:[Endothelial factors and thrombocyte function]. 177 33

We describe a rapid screening procedure to identify known DNA sequence changes in individuals diagnosed as having heterozygous familial hypercholesterolaemia (FH). The screening is made possible by combining a rapid DNA extraction protocol and small scale polymerase chain reaction DNA amplification, followed by oligonucleotide melting or restriction enzyme digestion. We have screened for two different mutations; firstly a mutation in the apolipoprotein B (apo B) gene that results in the substitution of glutamine (Gln) for arginine (Arg) at amino acid residue 3500 (apo B3500 mutation). Apo B is the principal component of the protein moiety of low density lipoprotein (LDL) and the mutation reduces the affinity for the LDL receptor (LDL-R). Secondly we have screened for a point mutation in the LDL-R gene itself that creates a new Pst I restriction enzyme site. This mutation in the LDL-R gene (LDL-R664 mutation) results in the substitution of leucine (Leu) for proline (Pro) at amino acid 664 and is known to slow processing of the LDL-R precursor to the mature form and to reduce the affinity of the receptor on the cell surface for LDL. In 77 unrelated patients with a clinical diagnosis of FH two out of 77 (2.6%) were positive for the apo B3500 mutation. Three (3.9%) were positive for the LDL-R664 mutation. Thus these two mutations might account for 5-6% of patients in the U.K. with a clinical diagnosis of FH (5000-6000 people).(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1991 Aug
PMID:Rapid screening for specific mutations in patients with a clinical diagnosis of familial hypercholesterolaemia. 179 40

The plasma concentration of lipoprotein (a) [Lp(a)] is correlated with the risk of atherosclerosis. It is a lipoprotein particle consisting of apoprotein (a) [Lp(a)] is correlated with the risk of atherosclerosis. It is a lipoprotein particle consisting of apoprotein (a) [apo(a)], a protein showing considerable amino acid sequence identity with plasminogen. bound to low-density lipoprotein. The apo(a) portion of Lp(a) was recently shown to have serine-proteinase-type amidolytic activity and to be able to degrade the adhesive glycoprotein fibronectin. To characterize this enzyme activity further, we used chromogenic peptide substrates and inhibitors. Of the substrates tested, those with arginine at the scissile bond [N-alpha-benzoyl-L-Arg p-nitroanilide (pNA), N-alpha-benzoyl-Ile-Glu-Gly-Arg-pNA, N-alpha-benzyloxycarbonyl-Arg-Gly-Arg-pNA] gave the highest hydrolysis rates. Synthetic substrates with plasmin specificity (Val-Leu-L-Lys-pNA and Val-Phe-L-Lys-pNA) were not hydrolysed by Lp(a). Neither tissue plasminogen activator nor urokinase had any effect on the enzyme activity. The addition of antibodies to these plasminogen activators did not inhibit the enzyme activity of Lp(a). Inhibition experiments with phenylmethanesulphonyl fluoride, carbodi-imide, dichloroisocoumarin and competitive peptide inhibitors demonstrated that Lp(a) has enzyme activity that closely resembles that of serine proteinases. Whether this serine-proteinase activity of Lp(a) plays any role in the genesis of atherosclerosis remains to be established.
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PMID:Characterization of the enzyme activity of human plasma lipoprotein (a) using synthetic peptide substrates. 182 80

EDRF is a potent, endogenous vasodilator that is produced and released from endothelial cells and subsequently causes the relaxation of VSM through the activation of soluble guanylate cyclase and an increase in VSM cyclic GMP. Structurally, EDRF is likely to be NO or a related nitrogen oxide-containing compound. It is synthesized in endothelial and other cell types from L-arginine by a calcium-calmodulin and NADPH-dependent enzyme. Its action is very similar to the nitrovasodilators that act directly on VSM. EDRF is present in all vascular beds, large and small vessels, and in a wide range of species. Its role in human vascular physiology and pathophysiology is just beginning to be understood. EDRF is a potent endogenous vasodilator and inhibitor of platelet aggregation and adhesion. Its activity is impaired in hypertension and atherosclerosis, and its absence due to endothelial damage may play a role in cerebral and coronary vasospasm. It is a mediator of flow-dependent vasodilation, and its inhibition by hypoxia may contribute to the hypoxic pulmonary vasoconstrictor response. Endothelial cell damage and impairment of EDRF production may also contribute to acute and chronic pulmonary hypertension. A further understanding of the chemical nature and synthetic pathways of EDRF should lead to the production of analogs and antagonists, which may play an important role in future treatments for atherosclerosis, myocardial infarction, angina, hypertension, and other vascular diseases. The recent realization that EDRF serves as the second messenger for guanylate cyclase activation and cyclic GMP production in a variety of cell types outside of the cardiovascular system, including renal and respiratory epithelium, cerebellar neurons, macrophages, and adrenocytes, suggests even broader implications. The importance of EDRF to the anesthesiologist may go beyond an understanding of its role in cardiovascular physiological and pathophysiological states. Initial studies have shown that the endothelium may play a role in mediating the vascular actions of anesthetics, and that anesthetics can inhibit the production, release, or action of EDRF. How are these interactions mediated? Are there significant differences between anesthetics with regard to their effects on EDRF? Is there a clinically significant effect of anesthetics on basal activity of EDRF, or only in response to exogenous stimulation? Conversely, it is important to determine if alterations in endothelial cell function by various disease states such as hypertension, atherosclerosis, adult respiratory distress syndrome, cerebral vasospasm, and others cause changes in the vascular actions of anesthetics. The potential interactions of anesthetics with EDRF production and action in cell types other than the endothelium have not yet been explored.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endothelium-derived relaxing factor: basic review and clinical implications. 186 89

The endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) or a closely related nitrosothiol derivative, and is formed from the amino acid, L-arginine. NO is rapidly inactivated locally, released into the blood stream and instantly destroyed by haemoglobin. EDRF-NO and NO generated from vasodilator nitrates work by activation of soluble guanylate cyclase, elevating cyclic guanosine monophosphate (GMP) levels to cause vasodilatation and inhibition of platelet aggregation. Endothelium-dependent vasodilatation is attenuated in hypertension, atherosclerosis and diabetes through either loss of endothelium or deficient formation of EDRF-NO. In these conditions exogenous nitrates may substitute for a failing endogenous mechanism.
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PMID:Endogenous nitrates--implications for treatment and prevention. 187 72

Key discoveries in the past decade revealed that the endothelium can modulate the tone of underlying vascular smooth muscle by the synthesis/release of potent vasorelaxant (endothelium-derived relaxing factors; EDRF) and vasoconstrictor substances (endothelium-derived contracting factors; EDCF). It has become evident that the synthesis and release of these substances contribute to the multitude of physiological functions the vascular endothelium performs. Accumulating evidence suggests that at least one of the EDRFs is identical with nitric oxide (NO) or a labile nitroso compound, which is produced from L-arginine by an NADPH- and Ca(2+)-dependent enzyme, arginine oxidase. The existence of more than one chemically distinct EDRF has been proposed, including an endothelium-derived hyperpolarizing factor (EDHF). The target of EDRF (NO) is soluble guanylate cyclase (increase in cyclic GMP) while EDHF appears to activate a K(+)-channel in vascular smooth muscle. Recent data suggest that muscarinic receptor subtypes selectively mediate the release of EDRF(NO) (M2) and EDHF (M1). EDRF(NO) affects not only the underlying vascular smooth muscle, but also platelets, inhibiting their aggregation and adhesion to the endothelium. The antiaggregatory effect of EDRF is synergistic with prostacyclin, so their combined release may represent a physiological mechanism aimed at preventing thrombus formation. An additional proposed biological function of EDRF(NO) is cytoprotection by virtue of scavenging superoxide radicals. The endothelium can also mediate vasoconstriction by the release of a variety of endothelium-derived contracting factors (EDCF). Other than the unique peptide endothelin, the nature of EDCFs has not yet been firmly established. Autoregulation of cerebral and renal blood flow and hypoxic pulmonary vasoconstriction may represent the physiological role of endothelium-dependent vasoconstriction. Growing evidence indicates that the endothelium can serve as a unique mechanoreceptor, sensing and transducing physical stimuli (e.g., shear forces, pressure) into changes in vascular tone by the release of EDRFs or EDCFs. In physiological states, a delicate balance exists between endothelium-derived vasodilators and vasoconstrictors. Alterations in this balance can result in local (vasospasm) and generalized (hypertension) increase in vascular tone and also in facilitated thrombus formation. Endothelial dysfunction may also contribute to the pathophysiology of angiopathies associated with hypercholesterolemia and atherosclerosis.
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PMID:Endothelium-derived relaxing and contracting factors. 187 96

Familial defective apolipoprotein B-100 (FDB) is a recently identified, dominantly inherited genetic disorder, which leads to an increased serum level of low density lipoprotein (LDL) cholesterol with reduced affinity for the LDL receptor. It is postulated that this disorder results from a G to A mutation at nucleotide 10,708 in exon 26 of the apo B gene creating a substitution of glutamine for arginine in the codon for amino acid 3500. To investigate whether recurrent mutation has contributed to the high frequency of FDB, we have conducted a haplotype analysis in previously reported and newly detected FDB heterozygotes in Germany. 5 FDB families and 6 unrelated FDB heterozygotes were genotypes at 4 polymorphic sites in the 3' end of the apo B gene. These sites consisted of the diallelic markers XbaI, MspI, EcoRI and the hypervariable region (3'HVR). In 5 FDB families and 1 unrelated FDB heterozygote the arginine(3500)----glutamine mutation could be unambiguously assigned to the haplotype XbaI-/MspI+/EcoRI-/3'HVR48, in the other 5 FDB unrelated heterozygotes this finding was consistent with the combination of the genotype. The existence of the arginine(3500)----glutamine mutation on the same and supposedly rare allele suggests that the mutant alleles are identical by descent in our population. The fact that the same mutant allele was identified in North America and Austria suggests a common European origin of the arginine(3500)----glutamine mutation.
Atherosclerosis 1991 Jun
PMID:Familial defective apolipoprotein B-100: haplotype analysis of the arginine(3500)----glutamine mutation. 189 87


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