Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the vascular structure and endothelium-dependent relaxation in two genetic models of hypercholesterolemia: apolipoprotein E (apoE)-knockout mice and combined apoE/LDL receptor-double-knockout mice. Intimal area was increased markedly in proximal segments of thoracic aortas from apoE/LDL receptor-knockout mice [0.13 +/- 0.03 (mean +/- SE) mm2] compared with normal (C57BL/6J) mice (0.002 +/- 0.002 mm2, P < .05). Despite intimal thickening, the vascular lumen was not smaller in the aortas of apoE/LDL receptor-knockout mice (0.52 +/- 0.03 mm2) than in normal mice (0.50 +/- 0.03 mm2). In apoE-deficient mice, intimal thickening was minimal or absent, even though the concentration of plasma cholesterol was only modestly less than that in the double-knockout mouse (14.9 +/- 1.1 vs 18.0 +/- 1.2 mmol/L, respectively, P < .05). Relaxation of the aorta was examined in vitro in vascular rings precontracted with U46619. In normal mice, acetylcholine produced relaxation, which was markedly attenuated by the nitric oxide synthase inhibitor NG-nitro-L-arginine (100 microM). Relaxation to acetylcholine and the calcium ionophore A23187 was normal in apoE-deficient mice (in which lesions were minimal) but greatly impaired in the proximal segments of thoracic aortas of apoE/LDL receptor-deficient mice, which contained atherosclerotic lesions. Vasorelaxation to nitroprusside was similar in normal and apoE-knockout mice, with modest but statistically significant impairment in atherosclerotic segments of apoE/LDL receptor-knockout mice. In distal segments of the thoracic aorta of apoE/LDL receptor-deficient mice, atherosclerotic lesions were minimal or absent, and the endothelium-dependent relaxation to acetylcholine and calcium ionophore was normal. Thus, in apoE/LDL receptor-knockout mice (a genetic model of hyperlipidemia), there is vascular remodeling with preservation of the aortic lumen despite marked intimal thickening, with impairment of endothelium-dependent relaxation to receptor- and nonreceptor-mediated agonists. Atherosclerosis may be accelerated in the apoE/LDL receptor-double-knockout mouse compared with the apoE-knockout strain alone. We speculate that other factors, such as the absence of LDL receptors, may contribute to the differences in the extent of atherosclerosis in these two models of hyperlipidemia.
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PMID:Atherosclerosis, vascular remodeling, and impairment of endothelium-dependent relaxation in genetically altered hyperlipidemic mice. 940 99

1. There is accumulating evidence for a range of abnormalities in the nitric oxide (NO) signalling cascade in human cardiovascular disorders. 2. In the present review we assess the literature detailing such evidence in early (hyperlipidaemia) and end-stage (heart failure) disease, with emphasis on the mechanisms by which the disturbances are thought to occur. 3. Strategies for the correction of disturbed NO signalling in these states are reviewed and include both prescribed pharmacological interventions, such as lipid-lowering therapy and novel uses of angiotensin-converting enzyme inhibitors, as well as non-pharmacological interventions, such as exercise and dietary supplementation with L-arginine and n-3 polyunsaturated fatty acids. 4. In addition to a decreased production/function of NO, the possible detrimental effects of a chronic elevation in NO production in patients with liver cirrhosis, together with a novel use of antibiotics to correct this perturbation, is outlined.
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PMID:Restoration of nitric oxide function in human hyperlipidaemia, congestive heart failure and liver cirrhosis. 975 Sep 51

Homocysteine (Hcy) represents a branching point between the transsulfuration and transmethylation pathway of methionine. A large increase of plasma concentration of Hcy is observed in patients with inherited hyperhomocysteinemia. A moderated increase (above 10 microM) is also observed in various pathological conditions, such as arterial occlusion, hypertension, hyperlipidemia and chronic renal failure. While amino acids were largely studied using capillary electrophoresis with UV or laser-induced fluorescence detection (LIF), thiol-amino acids were not. In this work we present a new approach for testing homocysteine in human plasma using CE-LIF and fluorescein isothiocyanate. The low fluorescence yield of the fluorescein thiocarbamyl (FTC) thiol-amino acids limits, probably, the sensitivity of the detection to 8 x 10(-10) M (instead of 10(-12) M for FTC-arginine).
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PMID:Quantitation of homocysteine in human plasma by capillary electrophoresis and laser-induced fluorescence detection. 976 92

Much debate on the benefits and risks of cholesterol lowering to prevent coronary heart disease has focused on excess non-CHD mortality rates reported in some trials. Because of the wide variation in design of cholesterol-lowering trials and because the non-CHD mortality rate was not a controlled endpoint of statistical power in most published studies, it has been difficult to determine whether any excess mortality was due to certain therapies, to other mechanisms, or to chance. As a result, some investigators have performed retrospective analyses of pooled trial data in order to augment statistical power. Some investigators have hypothesized that the human brain is dependent on a constant supply of cholesterol from the circulation and that cholesterol loss in neuronal membranes, with the possible consequences of behavioral disorders and increased risk of accident and violent death. Indeed Weidner and Griffin suggest that low cholesterol is a marker for poor underlying health; physical illnesses are likely to cause depression and other negative emotional states, which are often accompanied by suppressed appetite and weight loss causing reduction in cholesterol levels. Such mental states may also increase the risk of non-CHD death, for example suicide. Rossouw reviews the evidence concerning non-CHD mortality in cholesterol-lowering trials and reports metaanalyses carried out for all trials combined. The findings indicated a significant (15%) increase in non-CHD mortality in all trials combined. However, this was not related to cholesterol lowering itself, because there was no increased risk in trials with > 10% cholesterol reduction, whereas there was a significant (22%) increase in trials with lesser degrees of cholesterol lowering. The publication of a large secondary prevention trial (4S) employing Simvastatin for cholesterol lowering supports the idea that cholesterol reduction itself does not have adverse effects on non-CHD mortality. The overview of all published trials demonstrates their effectiveness in reducing cholesterol and provides clear evidence of benefits on stroke and total mortality. A 10% reduction in cholesterol yielded about a 20% decrease in CHD mortality, which would be expected to result in about a 6% reduction in total mortality. Endothelium-dependent relaxations are reduced in hyperlipidemia and atherosclerosis. Exogenous L-arginine improves or restores the reduced endothelium-dependent relaxations. Moreover inflammation is associates with the initiation and progression of atherosclerosis. The fact of the matter is the Cardiovascular drugs already in clinical use or in development are able to interfere with certain aspects of endothelial function and may be useful in protecting the vessels and, hence, in preventing the development of cardiovascular disease.
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PMID:[All mortality by cause of death. The challenge of coronary prevention]. 1005 Jan 41

Hyperlipidemia contributes to the development of intimal hyperplasia and accelerated atheroma in vein bypass grafts. Dietary cholesterol reduction and oral supplementation with L-arginine have been shown to reduce accelerated atheroma in experimental vein grafts. This study extends these observations by examining the effect of the combination therapy of cholesterol reduction and L-arginine supplementation on the development of intimal hyperplasia in vein grafts in hypercholesterolemic animals. Thirty New Zealand White rabbits had a carotid vein bypass graft performed and were sacrificed at 28 days postoperatively either for morphology (light and electron microscopy) and videomorphometry, or for in vitro contractile studies. Twenty animals received a 1% cholesterol diet for 4 weeks prior to surgery. This diet was continued until harvest in ten animals. Ten cholesterol-fed animals received L-arginine supplementation (2 g/kg/day, p.o.) for 7 days preoperatively and thereafter until harvest and in addition were returned to a normal diet on the day of surgery. The last ten animals were controls (normal diet). Combined cholesterol reduction and L-arginine supplementation prevented accelerated atheroma in vein grafts, halted the change in enhanced smooth muscle cell contractility, and improved endothelial cell function. Early postoperative therapy targeting atheroma development in the high-risk patient could offer significant morphological and functional benefits.
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PMID:Combination therapy of cholesterol reduction and L-arginine supplementation controls accelerated vein graft atheroma. 1046 92

Hyperlipidemia has been associated with an increase in the incidence of atherosclerosis. The oxidation of low density lipoprotein (LDL) plays an important role in the initiation and progression of atherosclerosis, one of its effects being the inhibition of endothelium dependent relaxation (EDR). The elevated level of lysophosphatidylcholine (LPC) in oxidatively modified LDL has been shown to be a biochemical factor responsible for the impairment of EDR in vascular ring preparations. Several endothelium-derived modulators are thought to control vascular responsiveness. The present work examined whether acetylcholine (ACh)-induced EDR in rat aorta (pre-contracted with phenylephrine, PE) involved both endothelium-derived nitric oxide (EDNO) and endothelium-dependent hyperpolarizing factor (EDHF) and whether LPC inhibited either of these selectively. Indomethacin (10(-5) M), had no significant effect on EDR, indicating that products of cyclooxygenase, including prostacyclin, are not involved. Treatment with either N(W)-nitro-L-arginine methyl ester (L-NAME, 6.8 microM) to inhibit the production of EDNO or with elevated K+ (15 mM), to block the hyperpolarizing effect of EDHF impaired EDR considerably (each of these shifting the inhibitory dose-response relationship to ACh by almost one log unit); in muscles treated with both of these agents EDR was completely inhibited. In each of L-NAME- and K-treated muscles, the addition of LPC (20 microM) further impaired EDR. LPC did not independently raise the tone of resting- or PE-contracted aorta. We conclude that the inhibition of EDR of rat aorta by LPC involves the actions of both EDNO and EDHF.
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PMID:Inhibition of endothelium-dependent vascular relaxation by lysophosphatidylcholine: impact of lysophosphatidylcholine on mechanisms involving endothelium-derived nitric oxide and endothelium derived hyperpolarizing factor. 1048 17

Coronary hypersensitivity to serotonin promotes platelet aggregation and, therefore, the progression of the atherosclerotic process. This abnormality occurs in the early stages of coronary atherosclerosis when the responses to bradykinin are still preserved. To determine whether such changes also occur early after cardiac transplantation, intracoronary injections of bradykinin and serotonin were performed in 7 control patients, in 19 patients with dyslipidemia, and in 15 cardiac transplant recipients (1 year after operation). Coronary angiography was normal in the 3 groups. In the segments where serotonin effects were the most pronounced, the diameter changes were measured by quantitative angiography. Bradykinin (60, 200, and 600 ng) increased in the same way as the coronary diameters in the 3 groups; in contrast, serotonin elicited vasodilation only in the control group (7+/-3%, percentage of baseline) and vasoconstriction in the hyperlipidemic group (-9+/-2%) and in transplant recipients (-15+/-3%). After intracoronary infusion of L-arginine (40 mg/min for 14 minutes), serotonin-induced constriction was attenuated in the hyperlipidemic group but not in transplant recipients. Thus, the response to bradykinin is preserved in the early stages of graft vasculopathy. However, in contrast to patients with hyperlipidemia, the absence of an L-arginine effect on the responses to serotonin suggests the involvement of mechanisms other than a decrease in endothelium-derived nitric oxide availability. Immune processes promoting the release of endothelium-derived contracting factors such as endothelin and/or superoxide anion may play a role.
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PMID:Absence of L-arginine effect on coronary hypersensitivity to serotonin in cardiac transplant recipients. 1056 27

To investigate the relative roles of the LDL receptor- and non-LDL receptor-mediated pathways in the clearance of apolipoprotein E (apoE) variants in vivo, we have generated apoE2(Arg(158)-Cys) (apoE2) and apoE3-Leiden transgenic mice deficient for the endogenous mouse Apoe and Ldl receptor genes (Apoe-/-.Ldlr-/- mice). Unexpectedly, on the Apoe-/-.Ldlr-/- background, expression of neither apoE2 nor apoE3-Leiden results in a decrease of the hyperlipidemia. In contrast, serum cholesterol levels are increased by the introduction of apoE2 and apoE3-Leiden in Apoe-/-.Ldlr-/- mice (to 39.1+/-7.1 and 37.6+/-7.6 mmol/L, respectively, from 25. 9+/-6.5 mmol/L). In addition, in these transgenic mice, the serum triglyceride levels are substantially increased (to 9.6+/-7.0 and 5. 8+/-2.8 mmol/L, respectively, from 0.7+/-0.5 mmol/L), which is associated with a decreased efficiency of in vitro LPL-mediated lipolysis of circulating VLDL. The VLDL-triglyceride secretion rate is not affected by the expression of apoE2 or apoE3-Leiden on the Apoe-/-.Ldlr-/- background. These results indicate that in the absence of the LDL receptor, clearance of triglyceride-rich apoE2 and apoE3-Leiden-containing lipoproteins via alternative hepatic receptors, such as the LDL receptor-related protein (LRP) is inefficient. Although apoE2 and apoE3-Leiden are disturbed in binding to the LDL receptor in vitro, expression of 1 or 2 mouse Ldlr alleles in an apoE2.Apoe-/- or apoE3-Leiden.Apoe-/- background results in a gene dose-dependent decrease of the hyperlipidemia. Furthermore, overexpression of the LDL receptor via adenovirus-mediated gene transfer rescues the hyperlipidemia associated with apoE2 and apoE3-Leiden expression. These data indicate that in apoE2 and apoE3-Leiden transgenic mice, the LDL receptor constitutes the predominant route for clearance of VLDL remnants, carrying even poorly binding apoE variants, and that this pathway is functional despite an apoE-mediated disturbance in VLDL triglyceride lipolysis.
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PMID:Hyperlipidemia of ApoE2(Arg(158)-Cys) and ApoE3-Leiden transgenic mice is modulated predominantly by LDL receptor expression. 1059 74

We have previously demonstrated that bradykinin blocks hypertrophy of isolated cardiomyocytes: this is dependent on the release of nitric oxide from endothelial cells. In the present study, we investigated the influence of endothelial dysfunction on the antihypertrophic action of bradykinin. Angiotensin II (1 microM) induced a 34 +/- 2% increase in [3H]phenylalanine incorporation (P<0.001), an in vitro marker of hypertrophy, in adult rat cardiomyocytes co-cultured with bovine aortic endothelial cells. This response was blocked by bradykinin (10 microM), but restored by the nitric oxide synthase inhibitor. N(omega)-monomethyl-L-arginine (100 microM). However, the antihypertrophic effect of bradykinin in co-culture was abolished by 24 h pretreatment of endothelial cells with high glucose (25 mM, to mimic hyperglycemia) and attenuated by hydrogen peroxide (100 microM, to mimic oxidative stress). Pretreatment with oxidized low-density lipoprotein (100 microg/ml for 24 h, to mimic hyperlipidemia) was without effect. The hypertrophic response to angiotensin II was not modified by endothelial cell pretreatment. Furthermore, the ability of bradykinin to elevate cGMP (a marker for nitric oxide) in cardiomyocytes co-cultured with endothelial cells was attenuated by pretreatment with either high glucose or hydrogen peroxide. In conclusion, loss of the cardioprotective action of bradykinin against angiotensin II-induced hypertrophy was associated with impaired nitric oxide release from dysfunctional endothelial cells.
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PMID:Endothelial dysfunction limits the antihypertrophic action of bradykinin in rat cardiomyocytes. 1088 62

Familial combined hyperlipidemia (FCHL) is the most commonly inherited hyperlipidemia in man, with a frequency of +/-1% in the general population and approximately 10% in myocardial infarction survivors. A genomic scan in 18 Dutch FCHL families resulted in the identification of several loci with evidence for linkage. One of these regions, 1p36.2, contains TNFRSF1B which encodes one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-repeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function (P = 0.032), and, borderline, with apolipoprotein B levels (P = 0.064). Furthermore, in a case-control study, association was demonstrated since the overall CA-repeat genotype distribution was significantly different among 40 unrelated FCHL patients and 48 unrelated healthy spouse controls (P = 0.029). This difference was due to a significant increase in allele CA271 homozygotes in the FCHL patients (P = 0.019). Mutation analysis of exon 6 in 73 FCHL family members demonstrated the presence of a single nucleotide polymorphism with two alleles, coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271 and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. In conclusion, TNFRSF1B was found to be associated with susceptibility to FCHL. Our data suggest that an as yet unknown disease-associated mutation, linked to alleles 196M and CA271, plays a role in the pathophysiology of FCHL.
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PMID:Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia. 1095 45


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