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Query: UNIPROT:P06889 (Mol)
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The effect of combining chronic endothelial injury and intermittent meal feeding of a high and low cholesterol, coconut oil, peanut oil diet on plama lipid and lipoprotein content and on the formation of atherosclerotic lesions within the iliac-femoral artery of rabbits was studied. Alternate feeding of a 1 or 0.1% cholesterol, 3% coconut oil, 3% peanut oil diet for 3 to 14 weeks resulted in a 4- to 11-fold increase in plasma cholesterol with 59 to 79% of the plasma cholesterol eluting in a molecular weight fraction comparable to human low density lipoproteins (LDL). In the iliac-femoral artery, an atherosclerotic intimal lesion with an average cross-sectional area of 0.452 mm2 was present in 98% of the animals. The lesion was typically eccentric in location and contained both superficial- and deep-intimal lipid-filled monocyte-macrophages, extracellular lipid, smooth muscle cells, and extracellular connective tissue matrix. The relative percent lipid composition of the iliac-femoral lesion was 62% cholesteryl ester, 21% free cholesterol, and 17% phospholipid. Thus, we conclude that the combination of meal feeding a cholesterol/fat diet, dietary regimen and chronic mild endothelial injury in the rabbit results in (1) a diet-induced hypercholesterolemia in which LDL appear to be the predominant lipoprotein; and (2) a lesion within the iliac-femoral artery comparable in histologic and chemical composition to a human fatty streak.
Exp Mol Pathol 1991 Jun
PMID:Dietary and mechanically induced rabbit iliac-femoral atherosclerotic lesions: a chemical and morphologic evaluation. 206 Jun 6

Familial hypercholesterolemia is an inherited disease in humans that is caused by a deficiency in the receptor that mediates the internalization and degradation of low density lipoprotein. Patients that inherit two abnormal low density lipoprotein receptor alleles have severe hypercholesterolemia, advanced atherosclerosis, and life-threatening coronary artery disease that is refractory to conventional therapies. In this review, we discuss the prospects for gene therapy in the treatment of familial hypercholesterolemia.
Mol Biol Med 1990 Jun
PMID:Prospects for gene therapy of familial hypercholesterolemia. 221 9

The adhesion of leukocytes to endothelium is a physiological phenomenon which is the first step for leukocyte emigration. The adhesion can be dramatically increased in pathological situations such as inflammation and vascular diseases. The molecular basis of leukocyte-endothelium interaction has been largely investigated in the last ten years. Using monoclonal antibodies it is possible to characterize the leukocyte adhesion molecule (LeuCAM) also named CD11/CD18 complex. These molecules responsible for leukocyte adhesion are heterodimers consisting of a common beta subunit and different subunit CD11a/CD18 corresponding to LFA-1; CD11b/CD18 to Mac1/Mol; CD11c/CD18 to GP150-95. Beside these receptors, other leukocyte structures such as the fibronectin receptors are involved in the adhesive process. On the endothelial cell side specialized structures implicated in leukocyte adhesion have been identified. Structures like Intercellular Adhesion Molecule (ICAM) are expressed on endothelial cells in the absence of stimulation, while other receptors Endothelial Leukocyte Adhesion Molecule (ELAM) are only detectable on activated endothelial cells. Cytokines such as IL-1 induced the expression of ELAM, increased the number of ICAM and Human Leukocyte Antigens (HLA) DR, DP, DQ. In various pathological circumstances, namely extracorporeal circulation, Acute Respiratory Distress Syndrome (ARDS), hypercholesterolemia and diabetes mellitus increased leukocyte adhesion has been reported and is potentially responsible for vascular damage. Therefore, the modulation of leukocyte-endothelial cell interactions is a possible target for antithrombotic and antiatherosclerotic therapy.
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PMID:Leukocyte adhesion to endothelial cells. 226 8

Rabbits fed an atherogenic diet for 60 days resulted in high levels of plasma lipid peroxides as well as extreme hypercholesterolemia. Both levels stayed high until 35 days after the atherogenic diet stopped. At the same time, plasma PGI2 level was remarkably decreased while TXA2 and platelet aggregability were increased. Atherosclerotic aortas contain high levels of lipid peroxides associated with decreased PGI2 and increased TXA2 generation. Atherosclerotic plaques had the highest level of lipid peroxides and TXA2 while PGI2 production was the least, as compared with nonplaque tissue of the same artery and the normal arteries. The condition of normal arteries was just the reverse. There was a negative correlation between lipid peroxides and prostacyclin production, and a positive correlation between lipid peroxides and TXA2, in both plasma and aorta of rabbits. These results suggest that there is a close correlation between atherosclerosis, elevated lipid peroxides, and disturbances in PGI2/TXA2 balances.
Exp Mol Pathol 1988 Apr
PMID:Effects of lipid peroxides on prostacyclin and thromboxane generation in hypercholesterolemic rabbits. 328 Mar 42

Development of intimal necrosis is characteristic of advanced atherosclerotic lesions. In order to study metabolic alterations preceding cellular death, the concentration gradients of glucose, glycogen, ATP, and lactate were measured within the walls of rabbit carotid arteries which were transmurally stimulated by dc impulses. This experimental model allows the induction of lipid-free intimal myocyte proliferations usually void of necrosis and, under additional hypercholesterolemia, typical lipid-laden atheromas, which become necrotic after 5-6 weeks of stimulation. Frozen samples (1 X 3 mm2) obtained from normal arterial wall and from both types of plaques as well as from spontaneously occurring aortic lesions of the hypercholesterolemic rabbits were cut in consecutive slices (10 microns thick) parallel to the luminal surface from the intima toward the adventitia. Compared with normal media, the results show that in the neointima the concentrations of glucose and glycogen decreased whereas that of lactate increased, independent of whether or not hypercholesterolemia was induced. The ATP concentration in lipid-free plaques was comparable with that in normal media, but strongly decreased in lesions which developed in combination with hypercholesterolemia. These observations support the view that in the initial stages of plaque growth, the intimal cells reveal an increased energy turnover leading to a decreased glycogen content. The development of necrosis, however, seems to involve additional events associated with a decrease in ATP, obviously depending on the effects of lipids or lipoproteins in the cells of the arterial wall.
Exp Mol Pathol 1987 Jun
PMID:Metabolite concentration gradients in the arterial wall of experimental atherosclerosis. 359 2

The hypothesis was examined that hypercholesterolemia induces a decrease in arterial microsomal membrane fluidity. To investigate this hypothesis, the fluorescence anisotropy (r) of 1,6-diphenylhexa-1,3,5-triene was measured in aortic microsomes isolated from the intimal-medial (IM) and medial (M) layers of swine thoracic aortas. After 10 weeks of feeding a high fat (10% lard) diet, serum cholesterol increased 2.3-fold compared to 3.6-fold in pigs fed a similar diet supplemented with 2% cholesterol. Based upon differences in r, the membrane fluidity of the IM layer was significantly less than the M layers. The membrane fluidity of the IM layer was inversely related to the severity of hypercholesterolemia regardless of dietary treatment. There were no differences in membrane fluidity among the three dissected M layers and the membrane fluidity of these layers was refractory to changes in serum cholesterol. A decrease in the membrane fluidity of the IM layer may contribute to the abnormal regulation of vascular tone which underlies the development of vasospasm in atherosclerotic arteries.
Exp Mol Pathol 1987 Aug
PMID:Effects of hypercholesterolemia on the microsomal membrane fluidity of intimal-medial versus medial layers of swine aorta: implications for the pathogenesis of vasospasm. 360 45

The luminal surface properties of aortic and mitral valve endothelium in hypercholesterolemic rabbits were examined with the aid of cationic ferritin (CF), ferritin-lectins (FWGA, FRCA, FSBA), and low density lipoprotein-colloidal gold (LDL-Gold) conjugates. Based upon comparative studies with normocholesterolemic rabbit valves, the number of CF and wheat germ agglutinin (FWGA) particles per 100 nm of endothelial surface was found to be reduced in moderate hypercholesterolemia (450 mg/dl). Conversely, the number of Ricinus communis agglutinin (FRCA) and soybean agglutinin (FSBA) conjugates were increased. Quantitation of the CF and FWGA particles demonstrated that the endothelium lining of the valve surfaces (i.e., the arterial surfaces of the aortic cusps, AA, and the ventricular surfaces of the mitral cusps, MV) exposed to more turbulent hemodynamic conditions displayed the greatest densities of particle counts. Cholesterol levels of 400-500 mg/dl produced a loss of characteristic differences in the number of ferritin particles that existed between the two surfaces of a cusp. Especially prominent over the AA and MV surfaces, these changes represented a reduction in the anionic properties of the endothelial glycocalyx. Enzymatic digestion demonstrated the reduction in surface sialic acid residues to be one of the major factors responsible for these early changes at the blood-endothelium interface. More severe hypercholesterolemia (700-900 mg/dl) resulted in even further reductions in the number of ferritin particles over the AA and MV surfaces but enhanced the binding of LDL-Gold. Chondroitinase studies of these specimens demonstrated that the initial loss of sialic acids at moderate serum levels unmasks deeper lying components of the glycocalyx (e.g., sulfated glycosaminoglycans) and augments the attachment of LDL molecules to the endothelial surface. The findings of this study suggest that specific macromolecular changes in the endothelial glycocalyx in diet-induced hypercholesterolemia occur at vascular locales where hemodynamic forces such as eddy formations and blood stagnation impinge against the vascular wall.
Exp Mol Pathol 1986 Jun
PMID:A cytochemical study of the surface properties of aortic and mitral valve endothelium from hypercholesterolemic rabbits. 372 Sep 17

The effects of vitamin D and cholesterol-rich diets on rat aortas were examined. Examination by electron microscopy showed a widening of the subendothelial space and the presence in this space of amorphous substances as early as the second week into mild hypercholesterolemia. After further time elapsed, basement membrane-like substances, microfilaments, migration of mononuclear cells, and modified smooth muscle cells were seen in the subendothelial space. In the vitamin D group, the main electron microscopic finding was of medial smooth muscle cell changes, such as focal degeneration and matrix vesicles. However, calcification was not observed in our present study. In rats fed a cholesterol-rich diet plus vitamin D, changes associated with both the cholesterol-rich diet only and vitamin D only were seen.
Exp Mol Pathol 1986 Jun
PMID:Aortic changes induced by hypercholesterolemia and hypercalcemia in rats. 372 Sep 18

A new substrate optimized assay for acyl-CoA:cholesterol acyltransferase (ACAT) was developed that permits the accurate measurement of ACAT activity in normal arterial microsomes. The apparent Km and Vmax of ACAT with respect to oleoyl-CoA were determined to be 3 microM and 17.7 pmole min-1 mg-1. While the Km value is similar to other values reported in the literature, the Vmax is 5- to 8-fold higher. The higher Vmax is attributable to the saturation of ACAT with not only oleoyl-CoA, but also cholesterol. The observation that exogenous cholesterol was necessary for the determination of maximal ACAT activity indicates that under normal conditions the endogenous level of microsomal cholesterol does not saturate ACAT. Assay of ACAT in the presence and absence of exogenous cholesterol permits a qualitative assessment of the amount of cholesterol in the cholesterol substrate pool of ACAT. Using this approach, it was found that hypercholesterolemia results in the expansion of the cholesterol substrate pool of ACAT. Of the 21-fold increase in ACAT activity in atherosclerotic aortas observed in this study. 80% of the increase was attributable to expansion of the cholesterol substrate pool, while 20% was attributable to more enzyme. Notably, the increase in the amount of ACAT was observed after only 2 weeks of hypercholesterolemia.
Exp Mol Pathol 1986 Jun
PMID:Regulation of acyl-CoA:cholesterol acyltransferase activity in normal and atherosclerotic rabbit aortas: role of a cholesterol substrate pool. 372 Sep 21

The effect of dietary restriction (half of the control ration) on cholesterol biosynthesis was investigated in rabbits fed either standard or cholesterol-rich diets. Accompanying the amplification of hypercholesterolemia, additional disturbances of cholesterol metabolism were observed when cholesterol feeding was associated with dietary restriction. In the intestine, underfed rabbits showed a more marked inhibition of duodenal cholesterol biosynthesis from [14C]acetate following cholesterol feeding than rabbits on normal caloric ration. In contrast liver cholesterogenesis was equally suppressed in both groups receiving cholesterol-rich diets. Cholesterol biosynthesis from [14C]mevalonate was also inhibited by cholesterol feeding particularly in the duodenum of underfed rabbits. In addition cholesterol feeding induced a marked increase of the labeled esterified: free cholesterol ratio in the liver, demonstrating intensive esterification, this was enhanced by dietary restriction. The additional cholesterol which accumulates in the plasma and in various tissues in underfed rabbits is of dietary origin since the feedback control of cholesterogenesis by exogenous cholesterol was shown to be very effective in these animals.
Exp Mol Pathol 1985 Oct
PMID:Effect of dietary restriction on cholesterol biosynthesis in the liver and the intestine of cholesterol-fed rabbits. 404 45


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