Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gemfibrozil is a widely used drug prescribed to elevate serum high-density lipoprotein (HDL) cholesterol levels and lower triacylglycerols. The present study was done to determine if the drug would alleviate hypercholesterolemia in exogenously hypercholesterolemic (ExHC) rats. In the drug-treated ExHC rats, the serum non-HDL cholesterol levels were lowered and the ratio of the non HDL cholesterol to serum triacylglycerols was decreased to the extent seen in the drug-treated SD rats. Liver cholesterol and triacylglycerols were lowered in the drug-treated rats. There was also an increase in fecal excretion of neutral sterols and bile acids, particularly chenodeoxycholic and beta-muricholic acids. The drug elevated cholesterol 7 alpha-hydroxylase activity and mRNA abundance and acyl-CoA cholesterol acyltransferase activity in the liver, but did not influence low-density lipoprotein receptor mRNA level in the liver. Thus, gemfibrozil is effective in alleviating hypercholesterolemia in exogenously hypercholesterolemic rats, by partitioning hepatic cholesterol into biliary excretion.
Comp Biochem Physiol B Biochem Mol Biol 1998 Jul
PMID:Gemfibrozil reduces non-high-density lipoprotein cholesterol in exogenously hypercholesterolemic (ExHC) rats fed a high-cholesterol diet. 978 18

An abundant, widely dispersed, extracellular sequence repeat that contains a consensus YWTD motif is shown here to occur in groups of six contiguous repeats. Thirteen lines of evidence, including experimental and computational data, predict with p<3x10(-9) that the repeats do not form tandem domains, but rather each group of six repeats folds into a compact beta-propeller structure. The six beta-sheets are arranged about a 6-fold pseudosymmetry axis, and each repeat contributes loops to the faces surrounding the pseudosymmetry axis. Seven different endocytic receptors that contain from one to eight YWTD beta-propeller domains act as lipoprotein, vitellogenin, and scavenger receptors. In the low density lipoprotein receptor (LDLR), the many mutations in familial hypercholesterolaemia that map to the YWTD domain can now be interpreted. In the extracellular matrix component nidogen, the YWTD domain functions to bind laminin. Three YWTD domains and interspersed fibronectin type III (FN3) domains constitute almost the entire extracellular domain of the sevenless and c-ros receptor tyrosine kinases. YWTD domains often are bounded by epidermal growth factor (EGF) modules, including in the EGF precursor itself. YWTD beta-propellers have a circular folding pattern that brings neighboring modules into close proximity, and may have important consequences for the architecture of multi-domain proteins.
J Mol Biol 1998 Nov 06
PMID:An extracellular beta-propeller module predicted in lipoprotein and scavenger receptors, tyrosine kinases, epidermal growth factor precursor, and extracellular matrix components. 979 Aug 44

The metabolism (uptake and degradation) of peroxynitrite-modified beta-VLDL and native beta-VLDL labeled with [125I]iodine was studied in monocytes isolated from peripheral blood of hypercholesterolemic (HC) and normolipidemic rabbits (NC). The peroxynitrite-modified beta-VLDL uptake and degradation was up to 2-fold higher in monocytes from HC rabbits than monocytes from NC rabbits. In addition, monocytes from HC rabbits took up and degraded significantly more peroxynitrite-modified beta-VLDL than native beta-VLDL. In contrast, monocytes from NC rabbits took up both lipoproteins in a similar rate and degraded more native beta-VLDL than peroxynitrite-modified beta-VLDL. Our results suggest that hypercholesterolemia can affect monocyte metabolism enhancing foam cell formation by increasing the influx of peroxynitrite-modified beta-VLDL.
Biochem Mol Biol Int 1998 Oct
PMID:Increased metabolism of peroxynitrite-modified [125I] beta-VLDL by monocytes from hypercholesterolemic rabbits. 980 2

Inflammatory mechanisms are involved in the pathophysiology of cardiovascular disease and the present review focus us on the association between inflammation and microvascular endothelial dysfunction in the heart, i.e. reduced endothelium dependent vasodilation of coronary resistance vessels. This abnormality is caused by reduced bioactivity of nitric oxide (NO), and it is found in a variety of conditions, including ischemic heart disease, cardiac allograft vasculopathy, diabetes, hypercholesterolemia, and smoking. At the level of the myocardial microcirculation, reperfusion injury manifests itself as endothelial dysfunction, no-reflow, and increased permeability, which are all probably the result of reperfusion-induced augmentation of the inflammatory response. In other animal models of cardiovascular disease, inflammatory alterations have been described that can contribute to microvascular endothelial dysfunction and reactive oxygen species, neutrophils, tumour necrosis factor-alpha, and inducible NO synthase are among the mediators that have been incriminated. Circulating levels of inflammatory mediators may serve as molecular markers of cardiovascular disease, and antiinflammatory interventions hold some promise for future cardiovascular therapy.
J Mol Cell Cardiol 1998 Dec
PMID:Inflammatory alterations in the myocardial microcirculation. 999 May 27

Calcium binding epidermal growth factor-like domains (cbEGFs) are present in many extracellular proteins, including fibrillin-1, Notch-3, protein S, factor IX and the low density lipoprotein (LDL) receptor, which perform a diverse range of functions. Genetic mutations that cause amino acid changes within these proteins have been linked to the Marfan syndrome (MFS), CADASIL, protein S deficiency, haemophilia B and familial hypercholesterolaemia, respectively. A number of these mutations disrupt calcium binding to cbEGFs, emphasising the critical functional role of calcium in these proteins. We have determined the calcium binding affinity of two sites within a cbEGF pair (cbEGF12-13) from human fibrillin-1 using two-dimensional nuclear magnetic resonance (NMR) and fluorescence techniques. Fibrillin-1 is a mosaic protein containing 43 cbEGF domains, mainly arranged as tandem repeats. Our results show that the cbEGF13 site in the cbEGF12-13 pair possesses the highest calcium affinity of any cbEGF investigated from fibrillin-1. A comparative analysis of these and previously reported calcium binding data from fibrillin-1 demonstrate that the affinity of cbEGF13 is enhanced more than 70-fold by the linkage of an N-terminal cbEGF domain. In contrast, comparison of calcium binding by cbEGF32 in isolation relative to when linked to a transforming growth factor beta-binding protein-like domain (TB6-cbEGF32) reveals that the same enhancement is not observed for this heterologous domain pair. Taken together, these results indicate that fibrillin-1 cbEGF Ca2+ affinity can be significantly modulated by the type of domain which is linked to its N terminus. The cbEGF12-13 pair is located within the longest contiguous section of cbEGFs in fibrillin-1, and a number of mutations in this region are associated with the most severe neonatal form of MFS. The affinities of cbEGF domains 13 and 14 in this region are substantially higher than in the C-terminal region of fibrillin-1. This increased affinity may be important for fibrillin assembly into 10-12 nm connective tissue microfibrils and/or may contribute to the biomechanical properties of the microfibrillar network.
J Mol Biol 1999 Feb 26
PMID:EGF-like domain calcium affinity modulated by N-terminal domain linkage in human fibrillin-1. 1002 41

The endothelium synthesizes and releases several vasodilating factors, including nitric oxide, endothelium-derived hyperpolarizing factor, and prostacyclin. Under certain conditions, it also liberates vasocontracting factors. Thus, the endothelium plays an important role in regulating vascular homeostasis. Several intracellular mechanisms are involved in the synthesis of nitric oxide, including receptor-coupled G proteins, the availability of L-arginine, cofactors for endothelial nitric oxide synthase and the expression of the enzyme. Endothelial dysfunction by aging, menopause and hypercholesterolemia is involved in the development of atherosclerotic vascular lesions, and predisposes the blood vessel to several vascular disorders, such as vasospasm and thrombosis. Multiple mechanisms are apparently involved in the pathogenesis of the endothelial dysfunction in atherosclerosis. The reduced production of nitric oxide by the endothelium is caused by abnormalities in endothelial signal transduction, availability of L-arginine, cofactors for endothelial nitric oxide synthase and expression of the enzyme. Other mechanisms may also be involved in the impaired endothelium-dependent relaxations in atherosclerosis, including increased destruction of nitric oxide by superoxide anion, altered responsiveness of vascular smooth muscle, and concomitant release of vasocontracting factors. In addition to the treatment of the underlying risk factors, several pharmacological agents can improve endothelial dysfunction in atherosclerosis. Thus, the endothelium is a novel therapeutic target for the treatment of atherosclerotic cardiovascular disease.
J Mol Cell Cardiol 1999 Jan
PMID:Primary endothelial dysfunction: atherosclerosis. 1007 13

The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances (i.e. endothelium-derived relaxing factor (EDRF = nitric oxide, NO) and prostacyclin) and vasoconstrictor substances (i.e. thromboxane A2, free radicals, or endothelin). Using either agents like acetylcholine or changes in flow to stimulate the release of EDRF (NO), clinical studies have revealed the importance of EDRF in both basal and stimulated control of vascular tone in large epicardial coronary arteries and in the coronary microcirculation. The regulatory function of the endothelium is altered by cardiovascular risk factors or disorders such as hypercholesterolemia, chronic smoking, hypertension or chronic heart failure. Endothelial dysfunction appears to have detrimental functional consequences as well as adverse longterm effects, including vascular remodelling. Endothelial dysfunction is associated with impaired tissue perfusion particularly during stress and paradoxical vasoconstriction of large conduit vessels including the coronary arteries. These effects may cause or contribute to myocardial ischemia. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of EDRF or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized low-density lipoprotein (LDL). Increased plasma levels of oxidized LDL have been noted in chronic smokers and are related to the extent endothelial dysfunction, raising the possibility that chronic smoking potentiates endothelial dysfunction by increasing circulating and tissue levels of oxidized LDL. In heart failure, cytokines and/or reduced flow (reflecting reduced shear stress) may be involved in the development of endothelial dysfunction and can be reversed by physical training. Other mechanisms include an activated renin-angiotensin system (i.e. postmyocardial infarction) with increased breakdown of bradykinin by enhanced angiotensin converting enzyme (ACE) activity. There is evidence that endogenous bradykinin is involved in coronary vasomotor control both in coronary conduit and resistance vessels. ACE inhibitors enhance endothelial function by a bradykinin-dependent mechanism and probably also by blunting the generation of superoxide anion. Endothelial dysfunction appears to be reversible by administering L-arginine, the precursor of nitric oxide, lowering cholesterol levels, physical training, antioxidants such as vitamin C, or ACE inhibition.
J Mol Cell Cardiol 1999 Jan
PMID:Endothelial dysfunction in human disease. 1007 15

In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascular smooth muscle cells in response to acetylcholine is dependent on the anatomical integrity of the endothelium. Endothelium-derived relaxing factor was identified 7 years later as the free radical gas nitric oxide (NO). In endothelium, the amino acid L-arginine is converted to L-citrulline and NO by one of the three NO synthases, the endothelial isoform (eNOS). Shear stress and cell proliferation appear to be, quantitatively, the two major regulatory factors of eNOS gene expression. However, eNOS seems to be mainly regulated by modulation of its activity. Stimulation of specific receptors to various agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine, thrombin) increases eNOS enzymatic activity at least in part through an increase in intracellular free Ca2+. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although the precise mechanisms activating the enzyme remain to be elucidated. Phosphorylation and subcellular translocation (from plasmalemmal caveolae to the cytoskeleton or cytosol) are probably involved in these regulations. Although eNOS plays a major vasodilatory role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production could be responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be promoted by several risk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty streak infiltration of the neointima). Several mechanisms probably contribute to this decrease in NO bioavailability. Finally, a defect in NO generation contributes to the pathophysiology of pulmonary hypertension. Elucidation of the mechanisms of eNOS enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology of endothelial dysfunction, and could provide insights for new therapies, particularly in hypertension and atherosclerosis.
Cell Mol Life Sci 1999 Jul
PMID:Endothelium-derived nitric oxide and vascular physiology and pathology. 1044 89

The low-density lipoprotein receptor (LDLR) plays a major role in cholesterol homeostasis. Mutations in the regulatory region of the LDLR gene, although rare, have been shown to alter transcriptional activity of the gene and can cause familial hypercholesterolaemia (FH). In this study, a transition (c-->t) was identified at nucleotide position -59 within repeat 2 of the LDLR promoter in a South African FH patient of mixed ancestry. By screening 17 family members of the index case for this promoter mutation, two additional single base changes (-124c-->t and-175g-->t) were identified, located at recently described cis- acting regulatory sequences of the LDLR promoter. Both the-59c-->t and the-124c-->t transitions were identified in the normocholesterolaemic son of the index patient. Reporter plasmids containing the normal and mutant promoter fragments were constructed by directional cloning. Transcription studies using a luciferase reporter system demonstrated that the-59c-->t mutation significantly reduces promoter activity in both the presence and absence of sterols ( approximately 40% of normal activity), while the-124c-->t variant increases transcription ( approximately 160%) of the LDLR gene. The intra-familial phenotypic variability observed amongst individuals with the-59c-->t mutation can probably be ascribed to allelic interaction, suggesting that variation in the LDLR promoter region may contribute significantly to the phenotypic expression of FH-related mutations in populations where these mutations prevail.
Hum Mol Genet 1999 Oct
PMID:Mutation -59c-->t in repeat 2 of the LDL receptor promoter: reduction in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia. 1048 71

Atherosclerosis is the leading cause of death in North America. It is characterized by thickening of the coronary artery wall by the formation of plaques, resulting in reduced blood flow. Plaque rupture and the consequent thrombosis may lead to sudden blockage of arteries and causing stroke and heart attack. In the last several decades, more than 250 factors associated with the development of coronary artery disease have been identified. Recently, a relationship between atherosclerosis and elevated homocysteine level in the blood has been established. The mechanism for the production of atherosclerosis by homocysteine has been investigated. When human hepatoma cells (HepG2) were incubated with 4 mM homocysteine, enhancements in the production of cholesterol and secretion of apolipoprotein B-100 were observed. The stimulatory effect on cholesterol synthesis was mediated via the enhancement of HMG-CoA reductase, which catalyzes the rate-limiting step in cholesterol biosynthesis. Cholesterol appears to play an important role in the regulation of apoB-100 secretion by hepatocytes. It is plausible that the increase in apoB secretion was caused by the elevated cholesterol level induced by homocysteine. The ability of homocysteine to produce a higher amount of cholesterol and promote the secretion of apoB would provide a plausible mechanism for the observed relationship between hyperhomocysteinemia and the development of atherogenesis and coronary artery disease.
Mol Cell Biochem 2000 Apr
PMID:Atherosclerosis risk factors: the possible role of homocysteine. 1088 40


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