Journal of atherosclerosis research最新文献

Twenty-four rabbits were fed standard rabbit pellets plus 2 % cholesterol. Twelve animals were exposed for 10 weeks to 28 % oxygen (atmospheric air + oxygen) and 12 animals to 21 % oxygen (atmospheric air). The degree of visible aortic atheromatosis and the aortic content of total cholesterol, phospholipids and triglycerides were significantly lower in the hyperoxic rabbits. Microscopic examinations supported the macroscopic findings.

The composition and synthesis of lipids from aortas of squirrel monkeys were studied following perfusion with [1-¹⁴C]acetate or [2-¹⁴C]mevalonate. Twenty-nine cholesterol-fed and 6 control monkeys were used. After 1 year on diet, the cholesterol-fed group had only slightly more aortic atherosclerosis than controls. In both groups fatty streaks and raised plaques were seen.

Fatty acid composition of phospholipids and triglycerides was similar in both groups. Substantial differences were noted in the cholesteryl esters; the principal change was an increase in cholesteryl oleate in aortas from cholesterol-fed monkeys.

In control aortas perfused with [l-¹⁴C]acetate phospholipid and triglyceride comprised approximately 90 % of lipid radioactivity. Among cholesterol-fed monkeys there was a slight increase in incorporation of newly synthesized fatty acids into aortic phospholipids with a slight decrease into triglycerides. Cholesteryl ester synthesis was increased approximately 6 times; oleic acid showed the greatest relative increase in synthesis.

[2-¹⁴C]Mevalonate incorporation into aortic lipids was similar for both groups. More than 95 % of the total lipid radioactivity was recovered in two fractions, one has been identified as squalene.

Perhaps most significant in these studies is the demonstration of metabolic changes (primarily an increase in cholesteryl ester synthesis) occurring in arteries only slightly more diseased than controls.

The effects of dietary carbohydrates on lipid metabolism have been investigated in rats maintained on diets containing 12 % glucose, fructose or sucrose and appreciable quantities of starch. The changes in hepatic rates of synthesis and catabolism of cholesterol and fatty acids as well as of triglycerides and phospholipids were studied to determine the relative influence of the three sugars on serum lipid concentrations. Marked increase in serum cholesterol results from feeding a sucrose diet, while elevation of serum neutral lipids is obtained with regimens containing fructose and sucrose. The effects are mainly due to the stimulation of rates of lipogenesis, associated with increments in the activities of enzymes of the hexose monophosphate oxidative pathway in the liver, coupled with relative lowering of the catabolic rate of specific lipid classes on respective carbohydrate regimens. Increased rates of triglyceride synthesis in the liver are responsible for elevated serum neutral lipid concentrations in rats on fructose and surcrose diets and are related to the high-α-glycerophosphate dehydrogenase activity in the liver of these animals. Evidence of induced phospho-fructokinase activity by fructose feeding has also been obtained and may be of significance in maintaining a high rate of supply of α-glycerophosphate via dihydroxy-acetone phosphate. Although glucose was found to stimulate hepatic cholesterolo-genesis, it reduced the serum cholesterol level by simultaneously maintaining a high rate of sterol catabolism in the liver. In spite of low sterol degradation rates in the liver of rats fed a fructose regimen, the serum cholesterol level was not significantly altered because hepatic cholesterol synthesis was depressed due to a relative increase in the rate of hepatic fatty acid synthesis from acetate.

The first clinical trials with a new aryloxy-type of hypolipidemic compound, the tetralin-derivative CIBA 13,437-Su, are reported. Various hyperlipidemic syndromes were treated in a total of 88 patients for periods up to 22 months.

With daily doses of 4–10 mg/kg, i.e. 300-600 mg per day, serum triglycerides and cholesterol were markedly lowered. The most pronounced effect was observed in hyperlipidemias of Types III, IV, and V of the Fredrickson-Lees classification. The pre-β-fraction appeared to be more readily lowered than the β-fraction, although the rather resistant hypercholesterolemia of Type II responded in all cases, yet to a lesser degree, and these patients received the higher doses. Slight transient increases in serum transaminases were observed in 7 out of 88 patients. The compound was very well tolerated subjectively. The results demonstrate that 13,437-Su is a very potent hypolipidemic agent.

Cholesterol esterification by lecithin cholesterol fatty acid transferase (acylase) was estimated in multiple layers of atherosclerotic human and rabbit aorta; lecithin-β-[1-¹⁴C]linoleic acid was used as substrate. Between 5 and 9 layers were obtained from the inside to the outside of the aortas; adjacent samples were examined histologically. Most transferase activity was located in the outer part of the atherosclerotic intima, but some was located in the inner media. Medial transferase activity must be derived from smooth muscle cells. Some activity in the atherosclerotic intima is probably located in lipid phagocytes; such cells are thought to be modified smooth muscle. The high activity in the outer part of the atherosclerotic intima may be partly due to the hyperplastic layer of smooth muscle cells in the zone.

In order to examine the role of aortic cells — particularly the mesenchyme — in promoting and sustaining atherosclerotic lesions, we studied cholesterol transfer in an experimental model. This model comprised a connective tissue compartment that directly exchanges with the blood department. The connective tissue was obtained by subcutaneously implanting polyvinyl sponges in the rat. Transfer of blood cholesterol to sponge tissue and release of sponge tissue cholesterol were measured by using labelled cholesterol. These transfers were calculated from this model as K₁ (uptake) and K₂ (release). These two values can be represented by B=K₁–K₂ where B is the change in cholesterol mass in the sponge tissue during the experimental period.

K₁ and K₂ flux values were obtained in two different experiments on the rat. The first experiment involved individual implants in 5 animals; whilst the second depended on implanting 7 rats with 4 implants each. The values K₁ and K₂ obtained in these two experiments were almost the same. Thus, cholesterol transfer could be measured and the ability of connective tissue to metabolize lipoprotein could be evaluated.

Previously we have shown correlations between the turnover rate of lipid in the aorta and sponge tissue; this emphasizes the importance of the connective tissue in the arterial wall. It is now possible to apply the present experimental model to investigate the local intra-arterial factors that operate in atherosclerosis.

Four groups of rabbits were fed for 10 weeks on diets composed of rabbit pellets and lard (2.5%) and containing either cholesterol (2 %), 2-ethyl-n-caproic acid (2.5 %), or both. Blood samples obtained at two-week intervals were analyzed for α- and β-lipoprotein lipids; at the end of the experiment, the aortic intima was graded for atheromatous plaques, and aorta and liver lipid contents were determined.

The major changes in serum lipids during cholesterol feeding occurred in the β-lipoprotein fraction, and the dietary feeding of 2-ethyl-n-caproate had no effect on any of the individual lipid fractions in either control or experimental animals. As with the serum lipids, 2-ethyl-n-caproate had no effect on increases in aortic free and esterified cholesterol due to cholesterol feeding. However, rabbits on 2-ethyl-n-caproate, plus lard, plus cholesterol diet showed aortic atheroma of 5.5—20.4 % (mean, 12.9 ± 2.4), while rabbits fed on lard plus cholesterol had aortic involvement of 20–83% (mean, 46.5 ± 11.2).

Analyses of platelet adhesiveness, blood viscosity and microvascular flow in conjunctival vessels were made in 100 patients, 65 of whom had thrombotic disease. Platelet adhesiveness (modified Salzman technique) was significantly increased (P < 0.001) to 41 and 40 %, respectively, in patients with acute myocardial infarction (n = 23) and with major artery occlusions (n = 15) when compared with controls (n = 16) which had 18 %. Blood viscosity was increased in all patients with arterial or venous thrombotic disease as well as correspondingly ill patients without thrombosis. The conjunctival microvasculature, as a reflection of atherosclerotic changes generally, showed abnormally advanced changes in 60 % of patients with arterial thrombotic disease and 35 % of patients with thrombophlebitis. It is concluded that platelet adhesiveness and vascular wall changes are significant contributing factors in arterial thrombotic disease. Increased blood viscosity in thrombotic disease is a secondary phenomenon.

Both thyroidectomized and methimazole-treated rats had lower concentrations of the sulfated acid mucopolysaccharides in their aortas. This decrease could be prevented or reversed by the administration of thyroxine. The same observations were made in hypophysectomized rats, and it was concluded that the acid mucopolysaccharide (AMPS) changes were due to a lack of thyroid hormone rather than to any changes in thyroid stimulating hormone (TSH) concentration. On the other hand, growth hormone specifically increased the chondroitin sulfate concentration in hypophysectomized rats, and this proceeded independently from the action of thyroxine. Cortisone decreased the amounts of chondroitin sulfate in rat aorta, but it had no effect upon the other AMPS fractions. Estradiol and testosterone administration as well as adrenalectomy and gonadectomy had no effect upon the aortic AMPS, and it was concluded that the rat aorta is mainly dependent upon thyroid hormone for the maintenance of its AMPS composition. The administration of methimazole prevented the accumulation of chondroitin sulfate in the aortas of lathyritic rats. This suggests that hypothyroidism decreases the biosynthesis of aortic AMPS.