Comparative primate atherosclerosis: II. A biochemical study of lipids,calcium, and collagen in atherosclerotic arteries

Arterial lipid, calcium, and collagen concentrations were determined for squirrel monkeys (Saimiri sciureus), African green monkeys (Cercopithecus aethiops), stump-tailed macaques (Macaca arctoides), and woolly monkeys (Lagothrix lagothricha) fed four types of diets with and without cholesterol for 42 mo. Comparisons were made with human arteries selected at several stages in the natural progression of atherosclerosis and the nonhuman primates were evaluated for their usefulness in the study of human atherosclerosis. Samples of normal artery, fatty streak, and plaque from the aortas of man and the nonhuman primates were fractionated by an ultracentrifugal method into a floating cholesterol layer termed “the nonbound cholesterol pool,” corresponding to the intra- and extracellular cholesterol thought to be capable of regression, and a “bound cholesterol pool” associated with the sedimenting arterial components such as membranes and connective tissue elements. The two physically distinct compartments of cholesterol were described and characterized within the atherosclerotic lesions.Most of the experimental diets fed the nonhuman primates increased the concentration of arterial lipids, especially esterified and nonesterified cholesterol. African green monkeys and stump-tailed macaques fed the atherogenic diet had greater accumulations of total cholesterol in the abdominal than thoracic aorta and were similar to man whereas squirrel monkeys were unlike man in that regard. Woolly monkeys fed the atherogenic diet had low concentrations of arterial cholesterol even though the arteries studied had intimal lesions. African green monkeys fed atherogenic diets had the most uniformly increased arterial calcium concentrations and were similar to man during the fourth and fifth decade of age as regards both arterial distribution and concentration. The stump-tailed macaques fed the atherogenic diet had 40–57% higher aortic hydroxyproline concentrations than controls indicating a very fibrous component comprising the lesion.Fatty streaks of African green monkeys, squirrel monkeys, and man had a similar concentration and distribution of total cholesterol in the lipid pools of aortic arch, thoracic aorta, and abdominal aorta; however, in that regard stump-tailed macaques were dissimilar and had low concentrations of cholesterol even though approximately 45% of the aorta was affected grossly with fatty streaks. Esterified cholesterol constituted the majority of the nonbound cholesterol pool of plaque in man and the nonhuman primates. On the basis of cholesterol distribution in atherosclerotic plaques, the stump-tailed macaque and the African green monkey seemed more similar to man.The results indicate that the African green monkey and the stump-tailed macaque would be the most useful of those species studied for investigating the lipid component of atherosclerosis. The African green monkey seems well suited for studies involving the mineral component of the lesion whereas the stump-tailed macaque appears useful for investigations on the proliferation of mesenchymal components of the artery wall and the resulting sclerogenic process.     

A Study of Atherosclerosis Regression in Macaca mulatta: III. Chemical Changes in Arteries From Animals With Atherosclerosis Induced for 19 Months and Regressed for 48 Months at Plasma Cholesterol Concentrations of 300 or 200 mg/dl

The influence of two levels of plasma cholesterol concentration on the long-term regression of atherosclerotic plaques in rhesus monkeys (Macaca mulatta) was studied. Forty-eight young adult male rhesus monkeys were fed an atherogenic diet for 19 months, then diets designed to maintain plasma cholesterol concentrations at 280-320 mg/dl (actual 316 ± 10 mg/dl; mean ± SEM) of 180-220 mg/dl (actual 204 ± 4 mg/dl). Twelve animals were killed after 19 months to evaluate the atherosclerosis produced. The remaining 36 monkeys were studied after 48 months of atherosclerosis regression. Significantly greater amounts of accumulated nonesterififed and esterified cholesterol were lost from the arteries of monkeys that underwent regression at about 200 mg/dl, in comparison with 300 mg/dl. Regression at both plasma cholesterol concentrations resulted in increased collagen and decreased elastin content in the thoracic aorta but not in the other arteries studied. After regression at 300 mg/dl there was no change (83%) in the frequency of calcification of the thoracic aorta, while at 200 mg/dl the frequency of calcification was reduced to 50%. When compared with monkeys whose athersclerotic lesions were produced in an identical manner but were regressed for only 24 months, after 48 months had increased cholesterol concenrations in the thoracic aorta and carotid artery but not the abdominal aorta of iliaco-femoral artery, regardless of the plasma cholesterol concentration. The lipid composition of the regressed plaque suggested a change in plaque lipid toward the character of extracellular deposits described physically as crystalline in nature. The physical state was influenced by the length of the regression period and the plasma cholesterol concentration during regeression. In the thoracic aorta, principally as a result of changes in elastin content, the collagen-to-elastin ratio increased between 24 and 48 months of regression. It is proposed that the differences in removal of cholesterol from the thoracic and abdominal aorta after 24 and 48 months of regression in animals at 300 mg/dl may be influenced by the rearrangement of connective tissue. On the basis of the lipid and mineral content of uncomplicated atherosclerotic plaques after 4 yers of regression, it appears that the plasma cholesterol concentration during the regression period is a signigicant factor influencing the extent of plaque regression as well as the potential for further progression.     

A study of atherosclerosis regression in Macaca mulatta: II. Chemical changes in arteries from animals with atherosclerosis induced for 19 months then regressed for 24 months at plasma cholesterol concentrations of 300 or 200 mg/dl

A clinically important question in people with existing atherosclerosis is whether a low concentration of plasma cholesterol attainable with diet or drug therapy influences preexisting atherosclerotic plaques and at what level of plasma cholesterol do these changes occur. Groups of young adult male rhesus monkeys were fed atherogenic diets for 19 months, then regression diets for 24 months. Regression diets contained sufficient cholesterol to maintain plasma cholesterol concentrations either at 302 ± 8 mg/dl, mean ± SEM (a concentration associated with a high risk for continued progression of atherosclerosis in man) or 194 ± 4 mg/dl (low risk for continued atherosclerosis development). A significantly greater amount of the accumulated arterial cholesterol, esterified cholesterol and phospholipid was removed in monkeys that underwent regression at 200 in comparison to 300 mg/dl. Decreases in arterial cholesterol in animals after 24 months at 200 mg/dl amounted to 100, 100, 93, and 96%, respectively, for carotid artery, thoracic aorta, abdominal aorta and iliaco-femoral artery in sharp contrast to decreases of only 80, 25, 56, and 72% in similar vessels of monkeys at the higher plasma cholesterol concentration. No major difference in arterial collagen or elastin was seen between the two regression groups. The frequency of mineralized plaques as assessed by aortic calcium accumulation was greater in the rhesus monkeys at the higher plasma cholesterol concentration during regression. Translated to human beings, these results suggest that for relatively uncomplicated fatty atherosclerotic lesions the plasma cholesterol concentration influences the degree of plaque regession and that significantly greater regression (as measured by a reduction in arterial lipid content) may be expected to occur at plasma cholesterol concentrations of 200 mg/dl as opposed to 300 mg/dl.     

Hyperlipoproteinaemia and atherosclerosis in rabbits fed low-level cholesterol and lecithin

Dutch-Belted rabbits were fed for 18 months an atherogenic semipurified gel diet containing 14% hydrogenated coconut oil and 0.06% cholesterol (approximately 0.15 mg/kcal) or a non-atherogenic basal gel diet containing the same ingredients but with no coconut oil or cholesterol. Rabbits fed atherogenic diet developed hypercholesterolaemia (means 733 mg/dl at 16 months) and plasma lipoprotein (LP) distribution shifted from a pattern in which high-density lipoproteins (HDL) predominated to one in which very-low-density lipoproteins (VLDL) were predominant. Total cholesterol/triglyceride ratio in d less than 1.006 LP changed from 0.3 to 1.8. Plasma cholesterol and LP distribution returned to normal in rabbits fed atherogenic diet for 18 months followed by atherogenic diet plus 3% soya lecithin for an additional 4 months. Rabbits fed atherogenic diet for 18 months had extensive, usually full circumference fibromuscular plaques in main branches of coronary arteries and all portions of aorta which compromised lumen area by almost 50%. These lesions were modified in rabbits fed atherogenic diet plus lecithin. The plaques lacked foam cells and cholesterol clefts, were less cellular with a distinct fibrous surface and occupied less space. Animals fed basal diet did not develop hypercholesterolaemia (means 86 mg/dl at 16 months), although distribution of plasma LP shifted slightly in favour of increased low-density lipoproteins (LDL) and decreased HDL compared with rabbits fed standard commercial diet. Basal diet rabbits had no coronary atherosclerosis and only minimal focal foam cell lesions in proximal aorta. Liver injury including fatty change, cholangitis and portal fibrosis occurred in animals fed atherogenic diet. Thus, rabbits fed appropriate diets low in cholesterol accumulate cholesterol-enriched LP in their plasma and develop lesions in abdominal aorta and main branches of coronary arteries which are similar to those in man. Also, in this experimental model, dietary lecithin promotes a return to normal of the LP distribution profile and removal of lipid from established atherosclerotic plaque.     

Hyperlipoproteinaemia and atherosclerosis in rabbits fed low-level cholesterol and lecithin.

Dutch-Belted rabbits were fed for 18 months an atherogenic semipurified gel diet containing 14% hydrogenated coconut oil and 0.06% cholesterol (approximately 0.15 mg/kcal) or a non-atherogenic basal gel diet containing the same ingredients but with no coconut oil or cholesterol. Rabbits fed atherogenic diet developed hypercholesterolaemia (means 733 mg/dl at 16 months) and plasma lipoprotein (LP) distribution shifted from a pattern in which high-density lipoproteins (HDL) predominated to one in which very-low-density lipoproteins (VLDL) were predominant. Total cholesterol/triglyceride ratio in d less than 1.006 LP changed from 0.3 to 1.8. Plasma cholesterol and LP distribution returned to normal in rabbits fed atherogenic diet for 18 months followed by atherogenic diet plus 3% soya lecithin for an additional 4 months. Rabbits fed atherogenic diet for 18 months had extensive, usually full circumference fibromuscular plaques in main branches of coronary arteries and all portions of aorta which compromised lumen area by almost 50%. These lesions were modified in rabbits fed atherogenic diet plus lecithin. The plaques lacked foam cells and cholesterol clefts, were less cellular with a distinct fibrous surface and occupied less space. Animals fed basal diet did not develop hypercholesterolaemia (means 86 mg/dl at 16 months), although distribution of plasma LP shifted slightly in favour of increased low-density lipoproteins (LDL) and decreased HDL compared with rabbits fed standard commercial diet. Basal diet rabbits had no coronary atherosclerosis and only minimal focal foam cell lesions in proximal aorta. Liver injury including fatty change, cholangitis and portal fibrosis occurred in animals fed atherogenic diet. Thus, rabbits fed appropriate diets low in cholesterol accumulate cholesterol-enriched LP in their plasma and develop lesions in abdominal aorta and main branches of coronary arteries which are similar to those in man. Also, in this experimental model, dietary lecithin promotes a return to normal of the LP distribution profile and removal of lipid from established atherosclerotic plaque.     

A study of atherosclerosis regression in Macaca mulatta. V. Changes in abdominal aorta and carotid and coronary arteries from animals with atherosclerosis induced for 38 months and then regressed for 24 or 48 months at plasma cholesterol concentrations of 300 or 200 mg/dl

Young adult male rhesus monkeys (Macaca mulatta) were fed an atherogenic diet for 38 months. After 38 months of atherosclerosis induction, a baseline group was selected and necropsied to determine the extent and severity of atherosclerosis before regression regimens were begun. The remaining animals were fed diets that varied in cholesterol concentration in order to maintain plasma cholesterol concentrations of approximately 200 or 300 mg/dl for either 24 or 48 months. The progression or regression of atherosclerosis in coronary arteries, abdominal aorta, and carotid arteries was determined by comparing them to the baseline group. Coronary artery atherosclerosis regressed in the majority of animals after 4 years but not after 2 years when plasma cholesterol concentrations were about 200 mg/dl. Among the animals maintained at plasma cholesterol concentrations of about 300 mg/dl, about half the animals progressed in the extent of coronary artery atherosclerosis while about half regressed. The majority of the animals that progressed in lesion extent were genetic hyperresponders to dietary cholesterol whereas those that regressed were predominantly hyporesponders, even though their plasma lipid concentrations were equivalent during the regression phase. The changes seen in atherosclerosis extent in the abdominal aorta were quite similar to the changes seen in coronary arteries. Changes at this site were not pronounced after 2 years, but after 4 years animals with plasma cholesterol concentrations of about 300 mg/dl progressed while the animals at 200 mg/dl were mostly unchanged. No evidence for atherosclerosis regression was found in the common carotid arteries or in the carotid bifurcations.     

Angiochemical and tissue cholesterol changes of Macaca fascicularis fed an atherogenic diet for 3 years.

Angiochemical and tissue cholesterol changes were investigated in Macaca fascicularis fed either an atherogenic containing 1 mg cholesterol/Cal or a control diet for 3 years. The thoracic and abdominal aortas and the carotid and femoral arteries were visually examined for the extensiveness of atherosclerosis and analyzed for lipid, collagen, elastin, and mineral content. Cholesterol accumulation in other tissues was assessed by measuring concentrations in liver, kidney, skin, and tendon. The cynomolgus macaques fed the atherogenic diet had between 77 and 97% of the intimal surface of all arteries studied affected with atherosclerotic lesions. The arteries of animals fed the atherogenic diet were between 1.6–2.5 times heavier than the arteries of control animals. This increased weight was attributed largely to collagen and elastin. When animals fed the atherogenic diet were compared with controls, significant increases in arterial total cholesterol, esterified cholesterol, phospholipid, calcium, phosphorus, and magnesium were seen. The liver, skin and tendon, but not the kidney, had significant increased concentrations of total and esterified cholesterol compared to control tissues. Comparison of our findings with the results of other studies of nonhuman primates indicates that the atherosclerotic plaques induced in the cynomolgus macaques are most nearly comparable to atherosclerosis in man, primarily because of the marked accumulation of mineral and connective tissue components.     

Antioxidant and anti-atherogenic activities of three Piper species on atherogenic diet fed hamsters

Atherogenic diet is known to induce high plasma lipid concentration, oxidative stress and early atherosclerosis. Antioxidants have potentials to counter the effect of atherogenic diet.The present research aims at evaluating the antioxidant and anti-atherosclerotic activities of three Piper species (Piper guineense, Piper nigrum and Piper umbellatum) on atherogenic diet fed hamsters.Hamsters divided into 8 groups: normal control, atherosclerotic control and six test groups. The normal animals fed normal rodent chow, the atherosclerotic control animals fed the same rodent chow supplemented with 0.2% cholesterol and 10% coconut oil (high cholesterol diet). The 6 test groups’ animals fed same diet as the atherosclerotic control group but with additional supplementation of 2 graded doses (1 and 0.25 mg/kg body weight, o.p.) of plant extracts for 12 weeks.The atherogenic diet induced a collapse of the erythrocyte antioxidant defense system (significant decrease in superoxide dismutase, catalase and glutathione peroxidase activities). Atherogenic diet also induced an increase in plasma total cholesterol, triglyceride, thiobarbituric acid reactive substances (TBARS), oxidation of low density lipoprotein cholesterol (LDL) and accumulation of foam cells in the aorta a hall mark for atherosclerosis. Administration of the Piper species prevented the collapse of the antioxidant system and the increase of plasma parameters maintaining them towards normality. The Piper species also prevented LDL oxidation by increasing the time (lag time) for its oxidation.The results suggest that these Piper species have significant antioxidant and anti-atherogenic effect against atherogenic diet intoxication.     

Atherosclerotic plaque regression in rhesus monkeys induced by bile acid sequestrant.

This study in 10 rhesus monkeys was made to determine whether the bile acid sequestrant, cholestyramine (CST), when added to an atherogenic diet would cause regression of atherosclerotic plaques induced by dietary means. Sequential plaque changes were evaluated by serial angiography, surgical exploration, biopsy, and autopsy. After 23 months on atherogenic diet (Period I) all animals developed fatty fibrous plaques. CST was then added to the diet of eight animals over the following 11 months (Period II) and at the end of this interval seven showed plaque regression. One animal appeared to show regression of atherosclerosis in abdominal aortic branches and progression in the internal carotid artery. Atherosclerotic disease progressed in two control animals which were continued on the atherogenic diet alone during Period II. Overall, CST was effective in lowering cholesterol level sufficiently to induce plaque regression. During Period II, fecal bile acid excretion increased eight fold while average serum cholesterol fell from 400 ± 13 to 237 ± 70 mg/dl. Plaque regression appeared related to level of serum cholesterol during Period II rather than to the magnitude of increase of fecal bile excretion.     

A study of atherosclerosis regression in Macaca mulatta. I. Design of experiment and lesion induction.

Rhesus monkeys were fed an atherogenic diet containing 40% of calories from lard and 1.0 mg/Cal cholesterol for either 19 months (Colony I) or 38 months (Colony II). At the end of the induction period the animals from each colony were divided into three groups (A, B, C) on the basis of total plasma cholesterol concentration during the induction period. Group A animals were killed at the end of the induction period for baseline observation of the extent and severity of atherosclerosis. Group B from each colony was fed a diet which maintained total mean plasma cholesterol concentrations between 280 to 320 mg/dl comparable to human beings with modest hyperlipoproteinemia. Group C from each colony was fed a diet which maintained total mean plasma cholesterol concentrations between 180 to 220 mg/dl, comparable to people who had modest hyperlipoproteinemia but were able to reduce plasma cholesterol concentrations by approximately 100 mg/dl using diet or drugs. Each group was further divided into two subgroups (B₁, B₂, and C₁, C₂). Animals from subgroup 1 were fed these diets for 24 months and animals from subgroup 2 were fed the same diet for 48 months.This report describes the clinical history, chemical analyses of arteries and the morphological extent and severity of atherosclerosis in arteries from animals of both colonies at the end of the induction period.     

Myocardial infarction in a large colony of nonhuman primates with coronary artery atherosclerosis.

Relatively few cases of myocardial infarction associated with coronary artery atherosclerosis have been described previously in macaques. In this study the authors report the prevalence and characteristics of coronary artery atherosclerosis and myocardial infarction in 10 rhesus (Macaca mulatta) and two cynomolgus (Macaca fascicularis) macaques that were fed atherogenic diets for 16 months or longer. Our findings show clearly that myocardial infarction occurs in macaques with diet-induced atherosclerosis. The frequency seems to be related to the species, composition of the atherogenic diet, and length of time fed the atherogenic diet. The myocardial lesions are remarkably similar to those described in human beings in terms of location and gross and microscopic characteristics. The characteristics of coronary artery atherosclerosis, including the occurrence of thrombosis, severe stenosis, mineralization, atheronecrosis, and sterol clefts, especially in animals fed the atherogenic diets for longer periods of time, also closely resemble those of the arterial lesions found in human beings. The greatest prevalence of myocardial infarcts was found in rhesus monkeys fed a cholesterol-containing diet with 40% of calories supplied by peanut oil and in cynomolgus macaques from Malaya that were fed the same amount of cholesterol with 40% of calories from lard. Electrocardiographic abnormalities as well as the occurrence of unexpected and relatively sudden death in several of these nonhuman primates are also consistent with signs frequently observed in human beings.     

Inhibitory effect of Ruta graveolens L. on oxidative damage, inflammation and aortic pathology in hypercholesteromic rats

The purpose of the study was to investigate the efficacy of methanolic extract of Ruta graveolens L. in reducing oxidative damage, inflammation and aortic pathology in hypercholesteremic rats. For the study rats were divided into three groups - control group, hypercholesteremic group and treatment group (20 mg MER/kg/d orally) - and were fed for 90 days. Serum total cholesterol, LDL-C, total WBC count, CRP level, TBARS, atherogenic index, activities of COX, 15 LOX in monocyte and serum myeloperoxidase were increased in cholesterol fed rats. Activities of antioxidant enzymes and the concentration reduced glutathione in liver and heart tissue and serum HDL-C were decreased in cholesterol fed rats. The results showed that level of total cholesterol, LDL-C, atherogenic index was decreased and HDL-C was increased in MER treated rats. Activities of antioxidant enzymes were found to be increased and the activity of MPO, COX and 15 LOX were decreased on supplementation with MER. Concentration of TBARS and total WBC count were decreased and GSH was increased on supplementation with MER. Histopathology of aorta of cholesterol fed rat showed marked alterations whereas the aorta of MER administrated rat showed no significant changes. These results suggested that MER reduces oxidative stress, inflammation and aortic pathology in hypercholesteremic rats. Thus the plant may therefore be useful for therapeutic treatment of clinical conditions associated atherosclerosis.     

Diet and vasectomy: effects on atherogenesis in cynomolgus macaques

We report here the effect of a moderately atherogenic diet on the progression of atherosclerosis among cynomolgus macaques that were either vasectomized or sham vasectomized. Both groups were compared to sham vasectomized monkeys fed a control Monkey Chow diet. As expected, slight hyperlipoproteinemia induced by the moderately atherogenic diet increased endothelial cell replication rates and resulted in the development of intimal lesions among sham vasectomized monkeys. Unexpectedly, vasectomy resulted in reduced leukocyte adherence to arterial surfaces, reduced endothelial cell replication rates in response to the moderately atherogenic diet, and at most arterial sites, smaller intimal lesions were produced. These data suggest that with slight hyperlipoproteinemia vasectomy may result in a small protective effect against atherosclerosis, while other studies have shown that marked hyperlipoproteinemia in cynomolgus macaques along with vasectomy results in exacerbation of atherogenesis.     

Dietary fish oil enhances monocyte adhesion and fatty streak formation in the hypercholesterolemic rat.

Using the rat model of atherosclerosis, the influence of dietary fish oil on early stages of atherosclerotic lesion formation was studied. Normocholesterolemic rats (serum cholesterol less than 100 mg/dl), moderately hypercholesterolemic rats fed cholesterol and cholic acid (serum cholesterol less than 400 mg/dl), and severely hypercholesterolemic rats fed cholesterol, cholic acid, and 2-thiouracil (serum cholesterol greater than 900 mg/dl) had their diets supplemented with 5% (w/w) "MaxEPA" fish oil for a period of 2 weeks. In each diet group safflower oil was used as a control for fish oil. Monocyte adhesion to the thoracic aorta and intimal foam cell formation were used to measure the extent of atherosclerotic lesion formation in each rat. Cholesterol and triglyceride levels were measured in both plasma and lipoprotein fractions. In normocholesterolemic rats, fish oil did not influence the morphology of the vessel wall. In moderately hypercholesterolemic rats, monocyte adhesion was the same irrespective of dietary oil, however, intimal foam cell formation was 2-fold higher in the fish oil-fed animals despite a reduction in serum cholesterol levels when compared to the safflower oil-fed animals. In severely hypercholesterolemic rats, monocyte adhesion to the vessel wall and intimal foam cell formation were both 4-fold higher in the fish oil compared with the safflower oil fed animals. These observations could not be attributed to differences in the plasma or lipoprotein profiles of safflower oil vs. fish oil fed rats. The results of this study suggest that dietary fish oil, when fed to hypercholesterolemic rats for a period of 2 weeks, enhances the rate of monocyte adhesion and fatty streak formation in the thoracic aorta.     

Coronary heart disease in rhesus monkeys with diet-induced coronary artery atherosclerosis.

Diet-induced coronary artery atherosclerosis develops in rhesus monkeys (Macaca mulatta). The goal of this study was to establish the rhesus monkey as an animal model of coronary heart disease (CHD). From a colony of 160 rhesus monkeys fed an atherogenic diet, we identified 14 monkeys with electrocardiographic and echocardiographic evidence of CHD. When compared with 14 rhesus monkeys matched for age, gender, and dietary history with normal electrocardiograms and echocardiograms, monkeys with CHD had higher arterial blood pressures (mean +/- SEM, 92 +/- 4 mm Hg vs 75 +/- 5 mm Hg, respectively), lower high-density lipoprotein cholesterol concentrations (mean +/- SEM, 1.70 +/- 0.25 mmol/L vs 2.32 +/- 0.28 mmol/L [66 +/- 10 mg/dL vs 90 +/- 11 mg/dl]), and lower A-l apolipoprotein concentrations (mean +/- SEM, 200 +/- 17 mg/dL vs 252 +/- 15 mg/dL). Monkeys with CHD tended to have higher total plasma cholesterol concentrations (mean +/- SEM, 11.6 +/- 1.55 mmol/L vs 9.36 +/- 0.93 mmol/L [450 +/- 60 mg/dL vs 362 +/- 36 mg/dL]) and higher low-density lipoprotein cholesterol concentrations (mean +/- SEM, 8.71 +/- 1.75 mmol/L vs 6.12 +/- 0.90 mmol/L [337 +/- 68 mg/dL vs 237 +/- 35 mg/dl]) than monkeys with normal electrocardiograms and echocardiograms. We conclude that rhesus monkeys, like human beings, develop CHD as a complication of coronary artery atherosclerosis. Furthermore, risk factors for CHD in rhesus monkeys and human beings are similar.     

Spider monkeys (Ateles sp.) as animal models for atherosclerosis research

Spider monkeys (Ateles sp.) were evaluated for their usefulness in research on atherosclerosis. These animals became only slightly hypercholesterolemic (increase from control serum cholesterol concentrations of about 200 mg/100 ml to about 290 mg/100 ml) when fed diets containing 1 mg of cholesterol/kcal (diets shown previously to produce marked hypercholesterolemia in most species of nonhuman primates).Both control and experimental monkeys had aortic fatty streaks and occasional lesions of the major branches of the coronary arteries. Cholesterol feeding for up to 48 months exacrebated the lesions only slightly.Biochemically, the atherosclerotic lesions of spider monkeys, as compared with other primates, have relatively less cholesterol ester and markedly more phospholipid.     

Increased atherosclerosis and glomerulonephritis in cynomolgus monkeys (Macaca fascicularis) given injections of BSA over an extended period of time.

A study was conducted to compare the effects of experimental immune complex disease on the development of glomerulonephritis and aortic and coronary artery atherosclerosis. Fourteen adult male macaques (Macaca fascicularis) were fed a mildly atherogenic diet. Ten of these animals were given repeated intravenous injections of bovine serum albumin (BSA), and the remaining 4 were given similar injections of saline. Three of the monkeys given BSA responded with a high antibody titer, 4 with a moderate titer, and 3 with a low level titer to BSA. In all 4 monkeys with the moderate antibody response glomerulonephritis developed, characterized by increased glomerular cellularity, electron-dense deposits in the glomerular capillary basal lamina, and deposits of IgG, IgM, C3, C4, and BSA. Glomerulonephritis was not seen in the other 6 monkeys given BSA or the 4 control monkeys. Aortic lesions seen at necropsy consisted of a few fatty intimal streaks with no differences between test monkeys (given BSA) and control monkeys (given saline). There was no correlation between total serum cholesterol concentration, high-density lipoprotein cholesterol concentration, or BSA antibody levels and the degree of aortic atherosclerosis. Immunochemical stains for immunoglobulins and complement components revealed increased intimal staining when intimal thickness increased. Medial staining for immunoglobulin and complement components appeared to be slightly increased in monkeys with moderately high-level titers of BSA. The extent of atherosclerosis in the coronary arteries of monkeys given BSA was greater than in the control animals. Differences in the extent and severity of the atherosclerotic lesions were most pronounced in the proximal portions of the main coronary arteries, suggesting an increased susceptibility of this site to immune-complex-exacerbated atherosclerosis. In addition to the increased lesion severity in monkeys given BSA, there were numerous granulocytes seen within, attached to, and penetrating into the intima of the coronary lesions. No correlation was seen between the development of glomerulonephritis and either aortic or coronary artery atherosclerosis.     

Overexpression of human lecithin:cholesterol acyltransferase in mice offers no protection against diet-induced atherosclerosis

Human lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the metabolism of cholesterol. We have used homozygous transgenic mice overexpressing the human LCAT transgene to study the effect of a "Western-type" atherogenic diet (30% fat, 5% cholesterol and 2% cholic acid) on their LCAT expression, activity, lipoprotein profile and tendency to develop atherosclerosis. The LCAT activity was 35-fold higher in serum of the homozygous transgenic mice than in murine control serum, and decreased 11-20% in the transgenic mice when fed the atherogenic diet. The total cholesterol and high-density lipoprotein cholesterol (HDL-C) concentrations were approximately doubled in the transgenic mice compared with the controls when both groups were fed a regular chow diet. In mice on the atherogenic diet, the triglyceride concentration decreased about 50% to the same level in transgenic and control mice. Total cholesterol and HDL-C concentrations increased and were 60-80% higher in the transgenic mice. The expression of LCAT mRNA in the liver was decreased by 49-60% in the transgenic mice when fed the atherogenic diet. The development of atherosclerosis was similar in transgenic and control mice. Thus, the 14- to 27-fold higher LCAT activity and the higher HDL-C concentrations in the homozygous LCAT transgenic mice had no significant protective influence on the development of diet-induced atherosclerosis.     

Atherosclerosis in Macaca mulatta: Histopathological,morphometric, and histochemical studies in aorta and coronary arteries of spontaneous and induced atherosclerosis

A comparative study of morphology, size, and histochemistry of the intimal lesions in aorta and coronary arteries of spontaneously occurring and cholesterol-induced atherosclerosis in rhesus monkeys has been carried out. A group of 30 normal monkeys was also investigated. Spontaneous atherosclerosis was noted in 10 of 55 adult monkeys autopsied serially; fatty streaks or atheroma in the aorta was noted in seven, fibrous plaque was noted in two, and diffuse intimal thickening was observed on one animal only. The coronary arteries showed fibrous intimal thickening without lipid in 8 of these 10 monkeys. There was fair to heavy deposition of acid mucopolysaccharides in the thickened intima along with proliferation of myointimal cells and collagen fibers. In the seven monkeys which were fed an atherogenic diet for 6 months, the aorta showed fatty streaking and atheroma in all animals. The coronary arteries also showed a variable degree of atherosclerosis but the lipid in the thickened intima was not marked. The atherosclerotic plaque height was not significantly greater than that in the spontaneous disease. These differences between spontaneously occurring and cholesterol-induced atherosclerosis in monkeys tend to indicate that the basic mechanism of lesion formation in the two states may be different.     

Removal of cholesteryl esters from diet-induced atherosclerotic lesions in two long-term studies in rhesus monkeys

In two long-term studies of dietary-cholesterol-induced atherosclerosis lesions in rhesus monkeys, we determined the fatty acid composition of cholesteryl esters in the arterial intima-media preparations. In the first study (2-year study) monkeys were fed an atherogenic diet for 2 years; in the second study, (5-year study), monkeys were fed the atherogenic diet for about 5.4 years. Dietary cholesterol was removed from regressed animals and the regression periods in the 2-year study were 30 and 52 weeks and in the 5-year study were 20, 30, 52, 101, and 191 weeks. In both studies in thoracic and abdominal aortic segments, the percent removal of 18:2 cholesteryl ester (CE) was small, whereas percent removal of 18:1 CE and other CEs was much higher. We postulate that 18:2 CE is not hydrolyzed to the extent comparable to 18:1 and other CEs in lesions. Perhaps 18:2 CE is not a preferred substrate for arterial neutral cholesterol ester hydrolase.