Cholestyramine treatment in early life of low-density lipoprotein receptor deficient Watanabe rabbits: decreased aortic cholesteryl ester accumulation and atherosclerosis in adult life.

Effect of cholestyramine treatment in early life of Watanabe heritable hyperlipidemic rabbits (an animal model lacking low-density lipoprotein receptor activity) on subsequent (6 months recovery) occurrence of natural atherosclerotic lesion and arterial cholesterol metabolism was investigated. Initial cholestyramine treatment decreased both plasma total cholesterol and HDL-cholesterol levels which normalized within 4 weeks after treatment was discontinued. At 9 months of age (age of occurrence of spontaneous atherosclerotic lesions), the extent of aortic atherosclerosis in cholestyramine pre-treated animals was modestly lower (P less than 0.05), as compared to controls, with a significant (P less than 0.05) decrease in aortic cholesteryl ester content. Furthermore, at the end of the recovery period aortic activity of acyl-CoA: cholesterol acyltransferase and neutral cholesterol esterase activity was significantly (P less than 0.05) lower in cholestyramine-pretreated animals. These studies show that early cholestyramine pre-treatment in a low-density lipoprotein receptor-deficient animal model causes persistent changes which might influence cholesteryl ester accumulation and atherogenesis in adult life, even after cholestyramine treatment is discontinued.

Antioxidant potential of specific estrogens on lipid peroxidation.

Coronary heart disease (CHD) is the leading cause of death in postmenopause. Estrogen administration in postmenopause lowers the risk of CHD by 50%. A variety of estrogen preparations are currently used in postmenopausal hormone replacement therapy. It is unknown, however, if structural differences in the estrogen molecule influence the cardioprotective effects of estrogens. In this communication we have shown that equine estrogens (especially equilin) exhibit higher antioxidant potency (as measured by fatty acids and sterols oxidation) when compared to estrone and estradiol-17 beta.

Short-term exposure to high dietary cholesterol in early life: arterial changes and response after normalization of plasma cholesterol.

Elevated serum cholesterol is an established risk factor for the development of atherosclerosis but the effect of high dietary cholesterol in early life on subsequent arterial response to atherogenic diet in adult life is unknown. Weanling rabbits were exposed for 6 wk to a diet containing 0.25% cholesterol, allowed to recover for 9 wk (at least 3 wk after normalization of plasma cholesterol), and subsequently rechallenged with cholesterol to determine atherogenic response. Enhanced activity of acyl-CoA-cholesterol-acyl-transferase in aorta induced by cholesterol feeding persisted even after normalization of serum cholesterol. When rechallenged with cholesterol for 3 mo, these animals displayed significantly (p less than 0.05) increased development of aortic atherosclerosis and accumulation of cholesterol esters when compared with control animals. Exposure to cholesterol in early life appears to cause persistent changes in cholesterol ester synthetic enzyme activity in aorta after normalization of plasma cholesterol and these residual effects might increase aortic response to subsequent cholesterol challenge in adult life.

Cholestyramine treatment in early life. Immediate and delayed effects on arterial cholesteryl ester metabolizing enzymes in the rabbit.

Feeding of cholestyramine-enriched diet to weaned normocholesterolemic rabbits resulted in: lowering of plasma cholesterol and distinctly decreased activity of aortic acyl-CoA cholesterol acyl transferase with no changes in aortic acid and neutral cholesteryl esterase activity. At 9 weeks after cessation of cholestyramine treatment enhanced activity of both aortic esterases were noted despite normalization of plasma cholesterol. No evidence for the presence of plasma factor influencing esterases activity was found in lipoprotein-free serum from cholestyramine-treated animals. These studies show that cholestyramine treatment in early life causes immediate and delayed changes in rabbit arterial cholesteryl ester metabolizing enzymes.

Studies on aorta during development. II. Differences in ontogeny of the key enzymes involved in cholesteryl ester synthesis and hydrolysis in rabbit aorta.

It is well known that cholesteryl ester accumulation is dramatically increased in the atherosclerotic artery. The enzymes acyl-CoA: cholesterol acyltransferase (ACAT), acid cholesteryl esterase (ACE) and neutral cholesteryl esterase (NCE) may play key roles in the accumulation of cholesteryl esters in the arterial wall. However, very little is known regarding the developmental pattern of the key enzymes involved in cholesteryl ester synthesis and hydrolysis. The total activities of ACAT, ACE and NCE were measured by radioassay using liposomal substrates in rabbit aortic homogenates. Our results indicate that ACAT activity decreases as a quadratic function with age (P less than 0.05). ACAT activity (pmol/100 mg protein/min) decreased from a high value in the fetus at term (63.3 +/- 7.4) to gradually lower values with increasing age. On the other hand, ACE activity (pmol/mg protein/min) was low in the fetus at term, and changed as a quadratic function with age (P less than 0.05) increasing gradually to higher activities with age up to a maximum at 12 weeks then decreased at 21 weeks. NCE activity (pmol/mg protein/min) increased dramatically from a low value in the fetus at term (3.34 +/- 0.48) to a maximum value at 1.5 weeks (14.65 +/- 2.73) then decreased as a linear function with increasing age up to 21 weeks (P less than 0.05). Plasma total cholesterol (mg/dl) also increased sharply from the fetal value at term of 98.5 +/- 5.2 to a maximum value at 1.5 weeks of 666.4 +/- 33.4, then decreased as a quadratic function with increasing age up to 21 weeks (40.8 +/- 6.7) (P less than 0.05). The free cholesterol content (microgram/mg protein) of the aortic tissue was initially high in the fetus (24.8 +/- 5.9) then increased with age. Examination of the ratio of synthesis to hydrolysis of cholesteryl esters as an index of enzyme activity units demonstrated a very high index in the fetus of 6.1 that rapidly decreased with increasing age in the young adult rabbit down to a value of 0.4 by 21 weeks of age. Correlation coefficients between enzyme activities, plasma cholesterol levels and aortic cholesterol levels indicated (a) a positive correlation of NCE activity with plasma cholesterol, (b) a negative correlation of NCE and ACE with aortic-cholesteryl ester content, and (c) no significant correlation of ACAT activity with either plasma cholesterol or aortic cholesterol content, indicating other factors are involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Age-related interrelationships of blood pressure and arterial sterol accumulation in spontaneously atherosclerosis-susceptible and atherosclerosis-resistant pigeons.

Interrelationships of arterial sterol accumulation and blood pressures were examined in age-matched White Carneau and Show Racer pigeons. It was found that the systolic blood pressure of White Carneaux changed from 155.0 mm Hg at nine months of age to 168.8 mm Hg at 17 months of age (P less than 0.005) while that of the Show Racers did not show any age-related increases. In White Carneaux, the total sterol content in the aorta increased by 43.6% from 9 months to 17 months of age (P less than 0.001) with major changes in the steryl ester fraction while no such changes were evident in the Show Racers. This indicates interrelationships of the arterial sterol content and blood pressure in the White Carneau pigeon.

Reverse cholesterol transport with acute exercise.

Physical activity has been shown to be inversely related to coronary heart disease (CHD). The role of high density lipoprotein (HDL) particles in the process of reverse cholesterol transport may be a link between exercise and the prevention of CHD. The aim of the present study was to evaluate the effects of acute exercise on cholesterol efflux (C-EF) from human monocyte derived macrophages overloaded with cholesterol and subsequently incubated with HDL fractions isolated from plasma. Ten males; five sedentary (NR) and five runners (R) exercised 30 min on a cycle ergometer at 60% of maximum oxygen consumption. HDL-C was higher in R when compared with NR (49.2 +/- 2.6 vs 36.8 +/- 4.6 mg.dl-1; P < 0.05). Plasma lipid profiles did not differ between groups and were unchanged with exercise. C-EF was higher to HDL obtained from NR compared with R before exercise (1.05 +/- 0.17 vs 0.59 +/- 0.09 microgram/mg protein, P < 0.05). Acute exercise increased HDL's ability to act as an acceptor of cellular cholesterol in R, whereas it decreased in NR. These preliminary studies suggest that functional changes in HDL fractions may differ in NR and R, and appear to be influenced by acute exercise.

Coffee extracts inhibit platelet aggregation in vivo and in vitro.

The effect of aqueous coffee extracts on platelet aggregation in humans (in vitro) and rabbits (both in vitro and in vivo) was investigated. Coffee extracts were found to have anti-aggregatory effects on in vitro platelet aggregation induced by ADP or arachidonate but not by collagen. Coffee extracts were also effective after intravenous administration in rabbits. The compound(s) responsible for these effects are water-soluble, heat-resistant, appeared to be different from salicylates, and might also be due to unidentified compounds besides nicotinic acid or known xanthines. Coffee extract and selected fractions decreased the conversion of [14C]-arachidonic acid to thromboxane B2 by the platelets. These studies show that coffee extracts contain compounds which are active in inhibiting platelet aggregation, a critical step involved in thrombosis and other vascular disorders.