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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of feeding fish oil (Menhaden) on the progression of rhesus monkey atherosclerosis was determined by feeding diets containing 2% cholesterol and either 25% coconut oil (Group I), 25% fish oil/coconut oil (1:1) (Group II), or 25% fish oil/coconut oil (3:1) (Group III) for 12 months (n = 8/group). The average serum cholesterol levels were 875 mg/dl for Group I, 463 mg/dl for Group II, and 405 mg/dl for Group III. HDL cholesterol levels were 49 mg/dl for Group I, 29 mg/dl for Group II, and 20 mg/dl for Group III. An average of 79% of the aortic intima was involved with atherosclerosis in Group I, 48% in Group II, and 36% in Group III. The aortas of both fish-oil groups (II or III) contained significantly less cholesterol (total, free, and esterified), as well as less acid lipase, cholesteryl esterase, and ACAT activities when compared to the coconut-oil group (I) (p less than 0.05). Microscopically, the aortic and carotid artery lesions were smaller in cross-sectional area and in thickness, and contained less macrophages in the fish-oil groups (II and III) when compared to the coconut-oil group (I) (p less than 0.05). This protective effect was not consistently enhanced by increasing the proportion of fish oil to 3:1 (Group III) over 1:1 (Group II). The results indicate that fish oil-containing diets reduce serum cholesterol levels and inhibit atherosclerosis even in the face of lowered HDL cholesterol levels when compared to a pure coconut oil/cholesterol diet in rhesus monkeys. Therefore, fish-oil diets exert effective protective control of progression of atherosclerosis during severe atherogenic stimuli.
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PMID:Fish oil inhibits development of atherosclerosis in rhesus monkeys. 367 3

Carnitine ester hydrolysis was observed in homogenates of normal rabbit (Oryctolagus cuniculus) aortas and in intact aortas from normal and cholesterol-fed rabbits using [14C]palmitoylcarnitine as a substrate. Hydrolytic activity was decreased approximately 50% in arterial tissue from cholesterol-fed rabbits and may account for the observation that carnitine esters accumulate in arteries of animals fed atherogenic diets. Long-chain acylcarnitines (C14-C18) were found to be moderate inhibitors of microsomal acylCoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26); short-chain acylcarnitine (C2-C10) and carnitine itself were not inhibitors. The data suggest that the increase in activity of arterial ACAT that characteristically parallels the development of atherosclerosis does not occur as a result of carnitine ester accumulation.
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PMID:Carnitine ester hydrolysis in arteries from normal and cholesterol-fed rabbits and the effects of carnitine esters on arterial microsomal ACAT. 650 6

Benzodiazepine drugs have been reported to have antiatherosclerotic effects in rabbits and roosters and to alter the pattern of circulating lipoproteins in man. The mechanism(s) of these effects has not been elucidated. The studies presented here indicate that diazepam, the most widely used benzodiazepine, is an inhibitor of cholesterol esterification by ACAT in vitro in atheromatous rabbit aortas, in microsomes isolated from atheromatous rabbit aortas, and in normal rat aortas. Diazepam also inhibited LCAT in plasma from man, monkey, rabbit, and rat, in vitro. The ability of diazepam to inhibit these enzyme systems may offer insight into possible in vivo mechanisms of action against atherosclerosis and of lipoprotein modification.
Atherosclerosis 1984 Mar
PMID:Diazepam inhibits cholesterol esterification by arterial ACAT and plasma LCAT, in vitro. 671 79

The local anesthetic lidocaine was studied for its effects on lipid metabolism in aortas from normal rats, rabbits, and cholesterol-fed (atherosclerotic) rabbits in vitro. Incubation of aortas in the presence of 3--5 mM lidocaine resulted in a statistically significant reduction in the incorporation of [14C]oleate into cholesteryl esters and phosphatidylcholine. Additionally, significant increases in [14C]oleate incorporation into the diglyceride fraction of atheromatous rabbit aortas was observed with a trend to greater incorporation into the diglyceride fraction of normal rat and rabbit arteries as well. The most significant overall effect of lidocaine was its inhibition (50--90%) of the arterial sterol esterification. Assays of acylCoA : cholesterol acyltransferase (ACAT, EC 2.3.1.26) in isolated arterial microsomes revealed that, in addition to local anesthetics (e.g., lidocaine), other membrane-active agents such as chlorpromazine and methoxyflurane inhibit ACAT; this suggests ACAT may be regulated by alterations in the biophysical properties of its membrane milieu.
Atherosclerosis 1981 Jul
PMID:Membrane-active agents. Effect of various anesthetics and chlorpromazine on arterial lipid metabolism. 725 30

The local anesthetics lidocaine, tetracaine, benzocaine and dibucaine were found to inhibit sterol esterification by acylCoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26) in the microsomal fraction isolated from rabbit aortas. In arterial microsomes, the incorporation of [14C]oleoylCoA into [14C]steryl esters was inhibited in a dose-dependent way by the anesthetics over the concentration range 0.25-5.0 mM. The potency of inhibition was dibucaine greater than benzocaine greater than tetracaine greater than lidocaine greater than procaine with inhibition of about 85% occurring with 0.25 mM dibucaine. Sterol esterification to [14C]oleic acid was also inhibited by the anesthetics in intact aortic tissue from the rabbit, dog, and rat. A detailed study of the effects of 5 mM lidocaine on lipid biosynthesis in the rabbit aorta in vitro revealed that lidocaine not only inhibited sterol esterification to [14C]oleate but stimulated [14C]oleate incorporation into glycerides.
Atherosclerosis
PMID:The effect of local anesthetics on arterial lipid metabolism. Inhibition of sterol esterification in vitro. 747 Feb 8

Inhibitors of the enzyme Acyl-CoA: Cholesterol Acyltransferase are regarded as potentially useful agents in the treatment of hypercholesterolemia and atherosclerosis. We report here a novel series of 2, 6-disubstituted-3-imidazolylbenzopyrane derivatives with significant in vitro ACAT inhibitory activity (IC50 range 0.05-0.5 microM). Compounds of this series such as 26 are examples of a new, structurally distinct class of potent ACAT inhibitors with high specificity for the aortic subtype of the enzyme. The structure-activity relationships of the 3-imidazolylbenzopyrane ACAT inhibitors were investigated by systematic manipulation of two regions of the parent compound 1 and the inhibitory activity resulted linked to the substituent in position 6 of the benzopyrane ring and modulated by the size of lipophilic substituents in position 2. Investigation of the mechanism of the inhibitory effect leads to the conclusion that these compounds act in a non-competitive fashion.
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PMID:Imidazolylbenzopyrane derivatives: a new class of acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors. 753 85

Atherosclerosis is a major death cause in western industrialized countries. A diagnosing system, medical prevention, and treatment of atherosclerosis is not sufficient so far. A direct acting antiatherosclerotic agent is eagerly waited. ACAT inhibitor approach could provide such an agent. In the formation of atherosclerosis, cholesteryl esters, which are the lipids which accumulate in atheromatous plaques by an aid of macrophages and smooth muscle cells, forming foam cells, may play an important role. ACAT enzyme is responsible for the acylation of cholesterol to cholesteryl esters, a transformation which can be essential in not only cholesteryl esters accumulation at arterial walls but also the absorption of cholesterol in the intestine and the excretion of cholesterol in the liver. From these points, ACAT inhibitors might work against atherosclerosis in three different ways: first, cholesteryl ester accumulation inhibition at arterial walls could be a direct antiatherosclerotic effect; second, cholesterol absorption inhibition at the intestine; and third, cholesterol excretion acceleration at the liver, while the later two effects would result in a reduction of blood cholesterol level--a major risk factor of atherosclerosis. Taking account of this discussion, the ACAT inhibitors would be potent antiatherosclerotic agents. Medicinal research has been contributing full strength to produce an ultimate compound. These efforts should provide a drug which will be useful to patients.
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PMID:ACAT inhibitors as antiatherosclerotic agents: compounds and mechanisms. 800 38

The mechanisms of action and selected agents for a variety of approaches to the treatment of atherosclerosis have been reviewed. In Table I, each approach is listed according to its primary physiological effect. This is a simplification, of course, and some agents, such as ACAT inhibitors, may have primary effects in all of these categories. As one goes from left to right, the benefit of each physiological effect becomes more speculative. There is no question of the benefit of LDL reduction, but less evidence exists for the clinical benefits of HDL elevation. With regard to direct anti-atherosclerotic effects, most approaches have yet to gather clinical data of any type. Perhaps as a result, the degree of medicinal chemistry effort in each area to date declines as one goes from left to right. This situation is changing rapidly, however. As evidence supporting the HDL hypothesis accumulates and knowledge of how to elevate HDL levels grows, very exciting opportunities for medical advances present themselves. Likewise, the knowledge base for nonlipid intervention is growing and very rapid advances are being achieved with the plaque-imaging techniques needed for evaluating such agents in man. Such results can only lead to greater opportunities for pharmacological intervention. Thus, in the future, much greater research effort will likely be dedicated to HDL elevation and nonlipid approaches. Through these efforts, physicians of the future should be armed with several complementary agents that can reduce the risk of cardiovascular disease in all patient populations.
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PMID:New approaches to atherosclerosis: an overview. 844 55

Five classes of lipid-lowering drugs are approved by the Food and Drug Administration (FDA) for use in the United States: nicotinic acid, bile acid sequestrants, fibric acid derivatives, reductase inhibitors, and probucol. None of the agents has an antiatherosclerotic indication. Cholestyramine and gemfibrozil have received indications for preventing complications of atherosclerosis, namely, myocardial infarction and coronary artery disease death. Foreseeable pharmacological strategies to reduce lipid-related cardiovascular risk might be divided into three categories. First, the present approach of lowering lipid and lipoprotein concentrations might be extended through modification of available agents (e.g., a more potent or soluble bile acid resin) or development of agents of novel mechanism (e.g., acyl-CoA:cholesterol acyltransferase [ACAT] inhibition or inhibition of cholesterol biosynthesis at a step other than HMG-CoA reductase). Second, blood lipids could be directly addressed outside of lipid-lowering strategies. Raising high density lipoprotein (HDL) cholesterol levels has not been fully explored, or the target might be modification of the lipoproteins themselves rather than their concentrations. Areas of particular interest in the latter regard are hepatic lipase activity, cholesteryl ester transfer protein activity, and differences between oxidized or otherwise modified low density lipoprotein (LDL) particles and normal LDL. Third, it may be possible to directly lessen the atherosclerotic potential of the vessel wall (e.g., through protecting it from the effects of certain growth factors or altering its state of relaxation.
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PMID:Dyslipidemia and atherosclerosis. A forecast of pharmaceutical approaches. 846 81

Differentiation of human promyelocytic leukemic HL-60 cells with 1,25-dihydroxyvitamin D3 (D3) results in macrophages which exhibit specific and saturable receptor-mediated processing of both native and modified low density lipoprotein (LDL). Analysis of binding kinetics demonstrated that macrophages bind LDL and acetyl-LDL with similar affinities, yet possess significantly different numbers of receptors (55 +/- 6 x 10(3) LDL receptors/cell vs 79 +/- 7 x 10(3) acetyl-LDL receptors/cell). D3-induced HL-60 macrophages challenged with LDL or acetyl-LDL exhibited suppression of HMG-CoA reductase activity as well as a significant induction in the incorporation of [14C]oleate into cholesteryl ester compared with macrophages incubated with lipoprotein depleted serum. Maximum increases in ACAT activity were obtained in macrophages incubated with 25-hydroxycholesterol plus LDL or acetyl-LDL. The increase in ACAT activity in macrophages challenged with acetyl-LDL paralleled the increase in cellular cholesterol content and the increase of oil red O lipid stainable material, imparting the macrophages with a foamy appearance. The data indicate that D3-induced HL-60 macrophages are a useful model for the study of lipoprotein--macrophage interactions as related to foam cell development and atherogenesis.
Atherosclerosis 1995 Sep
PMID:1,25-Dihydroxyvitamin D3-induced HL-60 macrophages: regulation of cholesterol and LDL metabolism. 854 49


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