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)

An important function of endothelium is to release PGI2, a prostaglandin produced from arachidonic acid that prevents platelet aggregation and causes arterial relaxation. Small amounts of other eicosanoids also are produced, but their role in endothelial function has not been elucidated. Much of the arachidonic acid present in the endothelium is obtained preformed from the plasma, either as FFA or from lipoproteins. Arachidonic acid is efficiently incorporated into endothelial lipids even when only relatively small amounts are available. In response to agonists, arachidonic acid is rapidly released from the endothelial phospholipids and converted to eicosanoids. Small amounts of eicosanoids also are continuously formed due to exposure of the endothelium to free fatty acid and lipoproteins containing arachidonic acid, without the need for any additional stimulus. Although the role of plasma lipid abnormalities has not been systematically investigated, there presently is little indication that hyperlipidemia interferes with endothelial arachidonic acid metabolism or the capacity of the endothelium to produce eicosanoids.
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PMID:Lipid and lipoprotein effects on endothelial eicosanoid formation. 306 Oct 5

Dietary fats play a critical role in atherogenesis and thrombosis. Both the amount of fat consumed and its composition affect various events associated with coronary artery disease. Dietary unsaturated fatty acids appear to reduce the incidence of these events, in particular polyunsaturated fatty acids (PUFAs), which exert markedly different effects on risk factors related to heart disease. The omega-3 (n-3) PUFAs, at high levels of dietary intake, significantly reduce hyperlipidemia and the production of the prothrombotic substance thromboxane, and they enhance the production of the platelet-antiaggregatory substance prostacyclin. Data from clinical trials indicate a significant reduction of levels of very low density lipoprotein (VLDL). The n-3 PUFAs also depress hepatic fatty acid and triglyceride synthesis and VLDL secretion. The n-3 PUFAs of fish oils displace arachidonic acid from tissue phospholipids and concomitantly increase n-3 PUFA levels, which inhibit thromboxane synthesis. Most significantly, in human subjects the antiaggregatory prostacyclin PGI3 is also synthesized and the net effect is enhanced antiaggregatory/antiadhesive activity. In addition, the chemotactic platelet adhesion-promoting substance leukotriene B4 is suppressed. These composite effects reduce atherogenesis and thrombosis. Fish oil n-3 PUFAs may also reduce blood pressure and blood viscosity. Through the combined vasodilatory effects via prostacyclin (PGI2 and PGI3), fish oils may improve peripheral circulation and thereby facilitate VLDL removal. The n-3 PUFAs of fish oils, by altering membrane fluidity in a specific manner, alter the activities of membrane-bound enzymes and may change receptor activity, specificity and signal transduction. Overall, these data indicate a beneficial role for n-3 PUFAs as part of a dietary approach to minimizing coronary artery disease.
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PMID:Effects of polyunsaturated fatty acids on factors related to cardiovascular disease. 331 46

The acute effects of fatty meals (900 kcal) rich in saturated (cream) or n-3 polyunsaturated (cod liver oil, CLO) fatty acids on human umbilical vein endothelial cells (ECM) and platelet behavior were studied. The ECM were incubated for 24 hours at 37 degrees C with either plasma or chylomicrons (CM) obtained 3 hours after the meals. The ability of the ECM to inhibit platelet aggregation (PIA) and the release of prostaglandin I2 measured as 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were measured after 24 hours of incubation, after stimulation and after freezing and thawing. Similar studies were done with CM from a patient with type V hyperlipoproteinemia. The release of 6-keto-PGF1 alpha was increased by postprandial plasma and by CM obtained after both meals. Plasma collected after CLO, but not after cream, increased PIA, whereas CM derived from all sources studied stimulated the PIA of ECM. No consistent correlation could be established between the release of 6-keto-PGF1 alpha and PIA. Increased platelet aggregation in platelet-rich plasma was always observed during postprandial hyperlipidemia.
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PMID:Effects of postprandial plasma and chylomicrons on endothelial cells. Differences between dietary cream and cod liver oil. 375 2

Extreme hyperglycemia (350 mg/dl) in rats results from streptozocin injection (50 mg/kg) and leads to a reduced aortic capacity for prostacyclin synthesis. Other complications such as hyperlipemia and alterations in body weight gain (loss or no gain) that might be responsible for the altered aortic prostacyclin synthesis occur concurrently. We injected neonatal rats (2 days of age) with intraperitoneal streptozocin to induce chronic mild diabetes (mean plasma glucose, 241 mg/dl) characterized in adult rats by normal body weight gain, normolipemia, and a physical appearance virtually indistinguishable from controls. Plasma insulin levels were reduced in rats with mild diabetes rats to 66% of control levels. A group of control and diabetic rats were given a 0.5% cholesterol diet for 7 weeks to induce hyperlipemia. Rats with diabetes and control rats given the cholesterol diet had elevated plasma insulin levels of 32% and 51%, respectively, and no alteration in plasma glucose levels (compared with respective controls), suggesting a state of insulin resistance. Aortic synthesis of 6-keto-PGF1 alpha from endogenous arachidonic acid was reduced in rats with mild diabetes and normolipemia or hyperlipemia. In contrast, the aortic conversion of exogenous arachidonic acid to 6-keto-PGF1 alpha was reduced only in rats with mild diabetes and hyperlipemia. Our results demonstrate that: (1) aortic prostacyclin synthesis is reduced in mild diabetes in the absence of alteration in plasma lipid levels and body weight gain; (2) aortic prostacyclin synthesis from endogenous arachidonic acid is more sensitive to diabetes than synthesis from exogenous arachidonic acid; (3) dietary cholesterol induces a state similar to insulin resistance and interacts with mild diabetes, resulting in reduced aortic prostacyclin synthesis from exogenous arachidonic acid.
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PMID:Altered aortic prostaglandin synthesis in a mild form of diabetes and the influence of dietary cholesterol. 623 73

A hypothesis of Gryglewski et al. explains the correlation between increased level of LDL and development of atherosclerosis by inhibition of PGI2 synthesis by increased peroxide content of LDL. The aim of the present paper was to examine this hypothesis. The major results are: 1) Preparation of LDL in the presence of .02% butylated hydroxytoluene did not reduce the lipid peroxide content of LDL from men and women and not change the inhibition or stimulation of the in vitro biosynthesis of PGI2 by LDL isolated from blood of men or women, respectively. 2) In the LDL and HDL, respectively, of healthy men we found nearly the same lipid peroxide levels (nmole malondialdehyde (MDA)/mg lipoprotein-cholesterol) as in the lipoproteins of male patients with hyperlipidemia type IIa or IV, but the peroxide concentration is three times higher in HDL as in LDL. 3) LDL isolated from healthy men inhibited in dose dependent fashion the generation of PGI2 from PGH2 by aortic microsomes whereas LDL from premenopausal women stimulated PGI2 formation even calculated as LDL lipid peroxides (in nM MDA/ml). The results call into question the hypothesis that diminished PGI2 formation by atherosclerotic vessels is related to inhibition of PGI2 synthetase by lipid peroxides present in LDL in the lesions. A new working hypothesis is presented that also the fatty acid pattern and the lipid class composition in the LDL are important for their influence on the PGI2 formation.
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PMID:Inhibition of prostaglandin I2 (PGI2) formation by LDL-cholesterol or LDL-peroxides? 639 33

In 13 type II hyperlipidemics (10 males and 3 females; mean age 50.2 +/- 10.6 years), in 10 type IV hyperlipidemics (7 males and 3 females; mean age 51 +/- 13.3 years) and in 23 healthy age- and sex-matched controls, the following parameters were measured: plasma cholesterol; plasma TG; plasma C-HDL; VLDL, separated in a preparative ultracentrifuge; C-LDL; Apo B, with immunoelectrophoretic method; platelet sensitivity to prostacyclin; TXB2 formation in PRP; TXB2 in serum. This study provides evidence for: 1. Reduced platelet sensitivity to prostacyclin, more evident in type II hyperlipidemia that provides an additional mechanism involved in increased platelet aggregation found in type II hyperlipidemia. 2. Enhanced TXB2 formation in PRP after thrombin stimulation (664.65 +/- 142.18 pmol/10(8) platelets) only in type II hyperlipidemics and such enhanced formation was positively correlated to C-LDL (r = 0.53; p less than 0.05) and to Apo B (r = 0.62; p less than 0.05); serum TXB2 formation rate was also increased in type II hyperlipidemia.
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PMID:Platelet sensitivity to prostacyclin and thromboxane production in hyperlipidemic patients. 675 32

The mechanism of thrombus formation in hyperlipidemia was studied. Attempts at artificial creation of an arterial thrombus in control rabbits stenosing the femoral artery by ligature were not successful unless ellagic acid was administered by injection. However, in rabbits with hyperlipidemia, mere creation of stenosis in the femoral artery resulted in a high percentage of thrombus formation. In rabbits with hyperlipidemia, both thromboxane (Tx) A2 biosynthesis in platelets and prostacyclin (PGI2) biosynthesis in the aorta were increased and these changes were noted at the level of cyclooxygenase in the arachidonic acid metabolic pathway. Therefore, these results suggest that thrombi are likely to be formed in hyperlipidemia and that such thrombus formation is due largely to platelet hyperfunction.
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PMID:The role of platelet hyperfunction in thrombus formation in hyperlipidemia. 680 87

A mammotropic pituitary tumor, MtT-F4, was implanted into male Fisher 344 rats for a period of 4 weeks. This tumor induced growth retardation, hyperlipidemia, hepatic hypertrophy and adrenal hyperplasia. Lipids were extracted from various tissues. In tumor-bearing rats, phospholipid concentration was found to be increased in plasma, spleen and testis. Distribution among the various phospholipid classes was similar to that of controls except in liver and heart, where phosphatidylcholine was increased at the expense of phosphatidylinositol and phosphatidylserine. The main difference was in the fatty acid composition of major phospholipids. The proportion of omega 6 fatty acids was lower and that of docosahexaenoic acid of the omega 3 series (22:6 omega 3) was higher in most tissues, especially in plasma, liver, heart and kidney. Concurrently, the urinary excretion of two endogenous metabolites of PGI2 (2,3-dinor-6-keto-PGF1 alpha and 6,15-diketo-13,14-dihydro-2,3-dinor-PGF1 alpha) was found to be increased significantly in tumor-bearing rats. The results raise the hypothesis that hormonal changes induced by the MtT-F4 tumor accelerate the conversion of arachidonic acid (20:4 omega 6) to prostaglandins. This effect, perhaps coupled with a diversion of linoleic acid (18:2 omega 6) towards other metabolic processes, would account for a partial depletion of membrane phospholipids in 18:2 omega 6 and for the reduced production of longer chain omega 6 unsaturated acids from 20:4 omega 6, creating a state of "relative essential fatty acid deficiency." As a result, the metabolism of omega 3 fatty acids is altered towards an enhanced production of 22:6 omega 3 which accumulates in the lipids of cell membranes to compensate for the depletion of unsaturated acids of the omega 6 series.
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PMID:Fatty acid composition of tissue phospholipids and prostaglandin excretion in hyperlipidemia induced in rats by implantation of the mammotropic pituitary tumor MtT-F4. 687 47

Effects of trapidil and other coronary vasodilators on retrograde blood flow in acute coronary-ligated dogs, isolated large and small coronary arteries of pig, platelet aggregation, biosynthesis of prostacyclin in isolated aortic rings and hyperlipemia in quails were investigated. Trapidil showed an increase in retrograde blood flow while dipyridamole, nifedipine, diltiazem and dilazep did not. Trapidil and nitroglycerin relaxed large coronary arteries, while dipyridamole, diltiazem, dilazep and adenosine relaxed small arteries. Trapidil, dipyridamole, diltiazem and aspirin protected against the secondary phase of ADP-induced platelet aggregation in guinea-pig platelet rich plasma more effectively than did nifedipine and dilazep. Trapidil and aspirin protected only against rabbit platelet aggregation as induced by arachidonic acid. Moreover, only trapidil protected against platelet aggregation as induced by prostaglandin G2-thromboxane A2 mixture. Trapidil and dipyridamole enhanced the platelet aggregation protection of prostacyclin. Trapidil also facilitated biosynthesis of prostacyclin more markedly than did the other drugs. Trapidil increased serum content of HDL cholesterol and significantly lowered serum content of triglyceride and the ratio of LDL cholesterol to HDL cholesterol in hyperlipemic quails. Dipyridamole, diltiazem, nifedipine and dilazep, however, showed little effect.
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PMID:[Pharmacological properties of trapidil: comparison with other coronary vasodilators (author's transl)]. 700 45

There is an abundance of information suggesting that prostaglandins are involved in the development and clinical expression of atherosclerosis. Many studies demonstrate a relationship between prostaglandins and the risk factors for peripheral and coronary artery disease. Thus, part of the mechanism by which hyperlipidemia, diabetes mellitus, smoking, hypertension, sex hormones, age, heredity, emotional stress and diet contribute to the development and progression of atherosclerosis may be through an imbalance between thromboxane A2 and prostaglandin I2. Recent studies show a temporal relationship between acute ischemic events (specifically, unstable angina) and a transcardiac increase in thromboxane B2, while others demonstrate a salutary effect of disaggregatory and vasodilatory prostaglandins in such patients. If prostaglandins and thromboxane prove important in ischemic vascular disease, attention will be directed at the correction of their pathologic imbalance. This may be accomplished by dietary manipulation as well as by the development of prostaglandin receptor antagonists or inhibitors of specific prostaglandin pathways.
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PMID:Prostaglandins and ischemic heart disease. 703 86


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