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

The study of the modes of action of lipid lowering drugs is important in order to evaluate their effects on the different lipid fractions and their possible secondary effects. These studies include: direct and indirect measurements of cholesterol absorption, the measurement of the principal enzymatic activities implicated in lipoprotein metabolism, especially those of lipases which play a fundamental role in the metabolism of particles rich in triglycerides and the inverse transport of cholesterol, and, finally, the measurement of intracellular enzyme activities. These last analyses are generally much more complex. Despite recent advances in all these investigative techniques, the mechanisms of action of many lipid lowering drugs remain obscure. Many have indirect modes of action like the inhibition of hydroxymethyl-glutaryl CoA by the fibrates and the mechanisms of action of the most recently introduced drugs are more complex than usually described. All these factors are important because the development of atherosclerosis depends on qualitative variations of the lipoproteins.
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PMID:[Mechanism of action of antilipemic drugs]. 128 87

Spontaneously hypertensive rat (stroke-prone) (SHRSP) has an interestingly low serum cholesterol level due to a reduced biosynthesis of cholesterol in the liver (Iritani, N., Fukuda, E., Nara, Y., and Yamori, Y. (1977) Atherosclerosis 28, 217-222). In this study, we examined the mechanism underlying the reduction of hepatic cholesterol biosynthesis in the rat. Our initial findings in SHRSP, as compared with normotensive Wistar Kyoto rat (WKY), showed that 1) the incorporation of [14C]acetate into cholesterol in the liver slices was markedly less, 2) 3-hydroxyl-3-methylglutaryl (HMG) CoA reductase activity was not reduced, and 3) the incorporation of [3H]mevalonic acid into both cholesterol and squalene was significantly less. The above initial findings suggested that the reduction in the hepatic cholesterol biosynthesis took place in one or more enzymatic processes starting with mevalonic acid and continuing to squalene. When the incorporation of [3H]mevalonic acid into phosphomevalonate derivatives was studied using an ion exchange column, only the radioactivity incorporated into isopentenyl-pyrophosphate (isopentenyl-PP) was less in SHRSP. Furthermore, the specific activity of diphosphomevalonate (mevalonate-PP) decarboxylase in the liver-soluble fractions was reduced 50% in SHRSP as compared with WKY. Kinetic studies using liver crude extracts indicated a lower Vmax value in SHRSP (SHRSP, 0.47; WKY, 2.05 nmol/min/mg), and an unchanged Km value (SHRSP, 18.2; WKY, 19.6 microM). The activity of mevalonate-PP decarboxylase was also found to be reduced in other tissues, including the brain, testis, small intestine, and cultured vascular smooth muscle cells. From the above observations, we concluded that the lower activity of mevalonate-PP decarboxylase was responsible for the reduced cholesterol biosynthesis in the liver of SHRSP.
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PMID:Liver mevalonate 5-pyrophosphate decarboxylase is responsible for reduced serum cholesterol in stroke-prone spontaneously hypertensive rat. 155 16

It has been supposed that prostacyclin (PGI2) and its analogues have important antiatherogenic effects. The aim of this work was to test the effect of PGI2 and 7-oxo-PGI2- (a stable analogue of PGI2) (6) treatment on the acyl CoA: cholesterol-acyltransferase (ACAT) activity in the aortic wall of rabbits. The rabbits had been previously fed with cholesterol and treated with PGI2 and 7-oxo-PGI2 intravenously. Cholesterol feeding increased ACAT activity compared to the control group which was not fed with cholesterol: 16.84 nmol/mg prot./h and 10.03 nmol/mg prot./h, respectively. PGI2 treatment of the cholesterol fed group did not cause a significant decrease, while 7-oxo-PGI2 treatment significantly decreased aortic ACAT activity compared to the cholesterol-fed control group; 14.31 nmol/mg prot./h; 11.53 nmol/mg prot./h and 16.84 nmol/mg prot./h, respectively. The decrease found in the ACAT activity after PGI2 and 7-oxo-PGI2 treatment are new data for the protective effect of these agents against atherosclerosis.
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PMID:Inhibition of ACAT activity after 7-oxo-PGI2 treatment in cholesterol-fed rabbits. 161 86

To test the hypothesis whether low density lipoprotein (LDL) poor in cholesteryl ester from patients with coronary artery disease (CAD) express reduced capacity to regulate cellular sterol and lipoprotein metabolism, we compared the abilities of CAD-LDL and control-LDL to suppress receptor-mediated LDL degradation; activate acyl-CoA: cholesterol acyltransferase (ACAT); and regulate sterol synthesis rates in HL-60 promyelocytic leukemic cells. The ratio of apolipoprotein B to cholesteryl ester was 23% higher for CAD-LDL than control-LDL (P less than 0.01), whereby CAD-LDL contained less cholesterol per particle than control-LDL and would be predicted to exert a reduced regulatory effect on sterol and lipoprotein metabolism than control-LDL at the same level of apo B protein. The results indicate that receptor-mediated 125I-LDL degradation rates were 43% higher for cells pre-incubated with CAD-LDL than with control-LDL (P less than 0.04), consistent with CAD-LDL having a lower ability to down-regulate LDL (apo B/E) receptor expression. When LDL degradation rates were expressed as a percentage of the rate of HL-60 cells incubated in lipoprotein-free medium, the mean LDL degradation rate for cells pre-incubated with CAD-LDL was 56% of untreated cells, while for cells incubated with control-LDL the average value was 41%. The data indicate that the suppression of receptor-mediated LDL degradation was proportional to the LDL cholesterol concentration in the medium. ACAT activity was 42% lower in cells pre-incubated with CAD-LDL as compared to control-LDL (P = 0.002), suggesting that the entry of cholesterol into the ACAT substrate pool was lower in cells pre-incubated with CAD-LDL. There was no significant difference in the rate of sterol synthesis from [14C]acetate between cells pre-incubated with CAD-LDL versus control-LDL. The data support the hypothesis that LDL from CAD patients exhibit a decreased ability to down-regulate apo B/E receptor activity which could in part account for the previously observed increase in LDL degradation by mononuclear leukocytes from CAD patients (Shi et al., Atherosclerosis, 85 (1990) 127).
Atherosclerosis 1991 Dec
PMID:Reduced regulatory capacity of low density lipoproteins from patients with coronary artery disease. 166 63

Cholesterol is converted to cholic acid and chenodeoxycholic acid by a series of reactions involving modifications to the steroid nucleus and oxidation of the side chain. These reactions can be affected by a number of inborn errors of metabolism. When this happens unusual bile acids or bile alcohols are synthesized; these can be identified using gas chromatography-mass spectrometry and fast atom bombardment mass spectrometry techniques. Two defects affecting the modifications to the steroid nucleus have been described; both present with cholestatic liver disease of neonatal onset. The better characterized of the two--3 beta-hydroxy-delta 5-C27-steroid dehydrogenase deficiency--leads to excretion of 3 beta-7 alpha-dihydroxy-5-cholenoic acid and 3 beta,7 alpha,12 alpha-trihydroxy-5-cholenoic acid in the urine. The liver disease improves dramatically on treatment with chenodeoxycholic acid. Deficient activity of 3-oxo-delta 4-steroid 5 beta-reductase is thought to be the cause of familial liver disease in some infants who excrete 7 alpha-hydroxy-3-oxo-4-cholenoic acid and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acid in the urine. However, diagnosis of this disorder is problematical; a similar pattern of metabolite excretion can occur as a result of liver damage caused by viruses or inborn errors of pathways unrelated to bile acid synthesis. Defective side chain oxidation in patients with cerebrotendinous xanthomatosis (CTX) leads to synthesis of bile alcohols such as 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol. Patients with CTX do not have cholestatic liver disease. Their major problems (neurological disease, atherosclerosis and xanthomata) are caused by accumulation of cholestanol and cholesterol in the tissues. Bile acid precursors are probably diverted into synthesis of cholestanol. Chenodeoxycholic acid suppresses the production of abnormal metabolites from cholesterol (by inhibition of cholesterol 7 alpha-hydroxylase) and leads to improvement in the neurological disease. Defective side chain oxidation also occurs in peroxisomal disorders but this time it leads to accumulation of C27 bile acids such as 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid (trihydroxycoprostanic acid, THCA). This compound is readily detected in the bile and plasma of patients with defects of peroxisome biogenesis. In patients with defects of a single peroxisomal beta-oxidation enzyme (the 3-hydroxyacyl-CoA component of the bifunctional protein or the thiolase), the major C27 bile acid in bile may be 3 alpha,7 alpha,12 alpha,24-tetrahydroxy-5 beta-cholestanoic acid (varanic acid).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inborn errors of bile acid metabolism. 174 14

Cholestyramine was administered to hamsters at 6 doses in the diet for 1 week. Plasma cholesterol, LDL + VLDL cholesterol and HDL cholesterol were measured after this period. Bile acid excretion was measured in faeces collected over the final 24 h of the experiment. A dose-response curve for each parameter measured was constructed using data from individual hamsters. For the bile acid and the cholesterol measurements a maximum response was observed at the highest doses. A correlation between the bile acids excreted over 24 h and the LDL + VLDL cholesterol showed that the maximum effect of cholestyramine on lowering plasma and lipoprotein cholesterol occurred at a submaximal excretion level of bile acids. Comparison of the efficiency of cholestyramine in reducing plasma cholesterol in the hamster with limited data in the dog and in man suggest that a greater lowering of plasma cholesterol is achieved in the dog and in man for an equivalent increase in bile acid excretion caused by the sequestrant. As is already known, cholestyramine treatment caused an increase in hepatic cholesterol 7 alpha-hydroxylase and HMG-CoA reductase activity. Interestingly in this study the novel observation was made that the bile acid sequestrant reduced the activity of hepatic acyl-CoA: cholesterol acyltransferase.
Atherosclerosis 1991 Aug
PMID:Cholesterol lowering and bile acid excretion in the hamster with cholestyramine treatment. 179 46

Pressure on the outside of arteries can cause physical and biochemical changes in the vessel wall of rabbits which are characteristic of atherosclerosis. It is hypothesized that occlusion of the vasa vasorum causes ischaemia of the arterial media which results in smooth muscle cell proliferation and cellular accumulation of cholesteryl esters. Hypoxia increases mRNA for platelet-derived growth factor in arterial wall cells and increases the activity of acyl CoA:cholesterol acyltransferase (ACAT). Such a mechanism may explain many of the anatomical, actuarial and environmental risk factors for atherosclerosis. Hypoperfusion may follow thrombosis of the vasa vasorum.
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PMID:Arterial wall hypoxia following thrombosis of the vasa vasorum is an initial lesion in atherosclerosis. 190 39

Pressure on the outside of arteries can cause physical and biochemical changes in the vessel wall of rabbits which are characteristic of atherosclerosis. It is hypothesized that occlusion of the vasa vasorum causes ischaemia of the arterial media which results in smooth muscle cell proliferation and cellular accumulation of cholesteryl esters. Hypoxia increases mRNA for platelet-derived growth factor in arterial wall cells and increases the activity of acyl CoA: cholesterol acyltransferase (ACAT). Such a mechanism may explain many of the anatomical, actuarial and environmental risk factors for atherosclerosis. Hyperfusion of the vasa vasorum may follow thrombosis.
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PMID:Arterial wall hypoxia following hyperfusion through the vasa vasorum is an initial lesion in atherosclerosis. 212 48

Sphingomyelin is found in plasma membranes and related organelles (such as endocytic vesicles and lysosomes) of all tissues, as well as in lipoproteins. Abnormalities in sphingomyelin metabolism have been associated with atherosclerosis, cancer and genetically transmitted diseases; however, except for Niemann-Pick disease, little is known about the mechanism for these disorders. Sphingomyelin biosynthesis de novo involves ceramide formation from serine and two mol of fatty acyl-CoA followed by addition of the phosphocholine headgroup. The headgroup appears to come from phosphatidylcholine, but other sources have not been ruled out. Factors that influence the rate of sphingomyelin synthesis include the availability of serine and palmitic acid, plus the relative activities of key enzymes of this pathway. Sphingomyelin turnover involves removal of the headgroup and amide-linked fatty acid by sphingomyelinases and ceramidases, respectively, which have been found in both lysosomes (with acidic pH optima) and plasma membranes (with neutral to alkaline pH optima). The enzymes of sphingomyelin turnover release ceramide and free sphingosine from endogenous substrates, which may have implications for the participation of a sphingomyelin/sphingosine cycle as another 'lipid second messenger' system.
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PMID:An update of the enzymology and regulation of sphingomyelin metabolism. 218 37

Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia.
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PMID:Management of dyslipidemia in NIDDM. 219 Jul 70


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