Atherosclerosis In Monkeys Research Articles

Identification of a mechanism for increased cardiovascular risk among individuals with low vitamin D concentrations.

The aim of this study was to investigate the plasma concentrations of vitamin D and its association with plasma lipid profiles. Plasma vitamin D3 and lipid concentrations were measured in 119 female cynomolgus monkeys (premenopausal, n = 49; ovariectomized, n = 70) consuming approximately 1,000 IU per day of vitamin D3. In a subset of the ovariectomized monkeys (n = 23), vitamin D3 was remeasured after 6 months. The concentrations of vitamin D3 were analyzed as a continuous variable and were divided at the median into high (≥48 ng/mL) versus low (<48 ng/mL) groupings. Among the 119 monkeys, the range of vitamin D3 concentrations was 24.0 to 95.2 ng/mL (mean ± SD, 48.5 ± 12.7 ng/mL). Plasma vitamin D3 concentration was positively associated with high-density lipoprotein cholesterol (HDL-C; P = 0.003). Monkeys in the high vitamin D3 group had a significantly greater plasma HDL-C concentration (57.9 mg/dL) than did those in the low vitamin D3 group (47.1 mg/dL; P = 0.001). Although the difference was not significant (P = 0.120), the monkeys in the high vitamin D3 group had a decreased total plasma cholesterol-to-HDL-C ratio compared with those in the low vitamin D3 group (5.4 and 6.2, respectively), potentially putting them at lower risk of atherosclerosis development. Given that the monkeys all consumed a diet replete in vitamin D3, it seems that individual differences in vitamin D absorption or metabolism may have determined whether the monkeys had high or low concentrations of vitamin D3. Lower vitamin D3 was associated with a more atherogenic lipid profile, a major risk factor for progressing to coronary artery atherosclerosis in monkeys and human beings.

120 Coronary Artery in Situ Helicobacter pylori and Its Association With Stress and Atherosclerosis in Monkeys

120 Coronary Artery in Situ Helicobacter pylori and Its Association With Stress and Atherosclerosis in Monkeys

Abstract: P719 NIFEDIPINE SUPPRESSES THE PROGRESSION OF ATHEROSCLEROSIS THROUGH THE ACTIVATION OF PPARΓ

Calcium channel blockers (CCBs) have been shown to improve clinical outcomes in atherosclerotic vascular disease. The mechanisms underlying the vasculoprotective effects of a third-generation calcium channel blocker, azelnidipine, are incompletely understood. We asked whether azelnidipine attenuates atherosclerosis in monkeys and mice beyond its blood pressure-lowering effects. Cynomolgus monkeys were randomized to three groups after 4 weeks of a high cholesterol diet: control group (no treatment) and 3 and 10 mg/kg daily azelnidipine; these doses have no effect on systemic arterial pressure or heart rate. Atherosclerosis was induced in the aorta by balloon injury, and the diet and treatment were continued for an additional 24 weeks. Azelnidipine did not affect blood lipid profiles, but reduced the development of atherosclerosis as detected by the elimination of local oxidative stress and reduced expression of monocyte chemoattractant protein-1 and platelet-derived growth factor. Azelnidipine also reduced the proliferation and migration of vascular smooth muscle cells in vitro. In atherosclerotic ApoE-knockout (ApoE-KO) mice fed a high cholesterol diet, azelnidipine but not amlodipine reduced the development of atherosclerosis. Neither drug changed the lipid profiles or systolic blood pressure of the mice. Thus, azelnidipine at clinically relevant doses exhibited anti-atherosclerotic effects in monkeys and mice independent of its blood pressure-lowering effects, suggesting that azelnidipine might be as a “vasculoprotective calcium channel blocker”.

Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo

Uptake of cholesterol from peripheral cells by nascent small HDL circulating in plasma is necessary to prevent atherosclerosis. This process, termed reverse cholesterol transport, produces larger cholesterol-rich HDL that transfers its cholesterol to the liver facilitating excretion. Most HDL in plasma is cholesterol-rich. We demonstrate that treating plasma with a novel selective delipidation procedure converts large to small HDL [HDL-selectively delipidated (HDL-sdl)]. HDL-sdl contains several cholesterol-depleted species resembling small alpha, prebeta-1, and other prebeta forms. Selective delipidation markedly increases efficacy of plasma to stimulate ABCA1-mediated cholesterol transfer from monocytic cells to HDL. Plasma from African Green monkeys underwent selective HDL delipidation. The delipidated plasma was reinfused into five monkeys. Prebeta-1-like HDL had a plasma residence time of 8 +/- 6 h and was converted entirely to large alpha-HDL having residence times of 13-14 h. Small alpha-HDL was converted entirely to large alpha-HDL. These findings suggest that selective HDL delipidation activates reverse cholesterol transport, in vivo and in vitro. Treatment with delipidated plasma tended to reduce diet-induced aortic atherosclerosis in monkeys measured by intravascular ultrasound. These findings link the conversion of small to large HDL, in vivo, to improvement in atherosclerosis.

DIETARY atherosclerosis in monkeys.

Dietary Atherosclerosis in Monkeys Get access Nutrition Reviews, Volume 12, Issue 1, January 1954, Pages 25–27, https://doi.org/10.1111/j.1753-4887.1954.tb03136.x Published: 01 January 1954

NUTRITION AND THE PATHOLOGY OF ATHEROSCLEROSIS IN MONKEYS

Journal Article Nutrition and the Pathology of Atherosclerosis in Monkeys Get access Nutrition Reviews, Volume 31, Issue 3, March 1973, Pages 100–101, https://doi.org/10.1111/j.1753-4887.1973.tb06004.x Published: 01 March 1973

Azelnidipine has anti-atherosclerotic effects independent of its blood pressure-lowering actions in monkeys and mice

Calcium channel blockers (CCBs) have been shown to improve clinical outcomes in atherosclerotic vascular disease. The mechanisms underlying the vasculoprotective effects of a third-generation calcium channel blocker, azelnidipine, are incompletely understood. We asked whether azelnidipine attenuates atherosclerosis in monkeys and mice beyond its blood pressure-lowering effects. Cynomolgus monkeys were randomized to three groups after 4 weeks of a high cholesterol diet: control group (no treatment) and 3 and 10mg/kg daily azelnidipine; these doses have no effect on systemic arterial pressure or heart rate. Atherosclerosis was induced in the aorta by balloon injury, and the diet and treatment were continued for an additional 24 weeks. Azelnidipine did not affect blood lipid profiles, but reduced the development of atherosclerosis as detected by the elimination of local oxidative stress and reduced expression of monocyte chemoattractant protein-1 and platelet-derived growth factor. Azelnidipine also reduced the proliferation and migration of vascular smooth muscle cells in vitro. In atherosclerotic ApoE-knockout (ApoE-KO) mice fed a high cholesterol diet, azelnidipine but not amlodipine reduced the development of atherosclerosis. Neither drug changed the lipid profiles or systolic blood pressure of the mice. Thus, azelnidipine at clinically relevant doses exhibited anti-atherosclerotic effects in monkeys and mice independent of its blood pressure-lowering effects, suggesting that azelnidipine might be as a “vasculoprotective calcium channel blocker”.

Mononuclear Leukocyte Mineralocorticoid Receptors

To the Editor: Takai et al have recently demonstrated a possible role of aldosterone in endothelial dysfunction since eplerenone strengthens the endothelium-dependent relaxation and prevents atherosclerosis in monkey fed with a high cholesterol diet but with normal aldosterone plasma levels.1 However, the title of the editorial commentary related to this article, “Eplerenone antagonizes atherosclerosis, but what is the agonist?,”2 is emblematic of the difficulty to relate eplerenone and normal aldosterone concentration to inflammation and atherosclerosis. Aldosterone has been involved in the genesis of inflammation. This process is preceded by peripheral blood mononuclear leukocytes (MNL) invasion, and it is still uncertain whether MNL are activated before tissue invasion or they are attracted in the site of inflammation by local factors. We have demonstrated that peripheral MNL of healthy subjects possess mineralocorticoid receptors (MR)3 that are sensitive to aldosterone in terms of oxidative stress induction.4 In particular, coincubation of MNL …

Eplerenone Inhibits Atherosclerosis in Nonhuman Primates

Aldosterone may be involved in the pathogenesis of atherosclerosis. We investigated the effect of eplerenone, a selective mineralocorticoid receptor blocker, on atherosclerosis in monkeys fed a high-cholesterol diet. Monkeys fed a high-cholesterol diet for 9 months were divided into 3 groups: those treated with a low dose of eplerenone (30 mg/kg per day); those treated with a high dose of eplerenone (60 mg/kg per day); and the placebo-treated group. The normal group consisted of monkeys fed a normal diet. There were no significant differences in blood pressure and cholesterol levels between the placebo- and eplerenone-treated groups. On the other hand, monocyte chemoattractant protein-1 and malondialdehyde-modified LDL were significantly higher in the placebo-treated group than in the normal group, whereas they were suppressed in the eplerenone-treated groups. The ratio of intimal volume to total volume by intravascular ultrasound analysis imaging of the aortas was dose-dependently lower in the eplerenone-treated groups than in the placebo-treated group. Acetylcholine-induced vasorelaxation was significantly weaker in the placebo-treated group than in the normal group, but the vasorelaxation was strengthened in the eplerenone-treated groups. A significant upregulation of angiotensin-converting enzyme activity was observed in the placebo-treated group, but the activity was suppressed in the eplerenone-treated groups. In conclusion, eplerenone may strengthen the endothelium-dependent relaxation and suppress angiotensin-converting enzyme activity in the vasculature, thus preventing the development of atherosclerosis in nonhuman primates.

Anticoagulant responses to thrombin are enhanced during regression of atherosclerosis in monkeys.

Diet-induced atherosclerosis in monkeys produces abnormal anticoagulant responses to thrombin, including decreased generation of activated protein C (APC). We tested the hypothesis that anticoagulant responses to thrombin increase toward normal during regression of atherosclerosis. Six cynomolgus monkeys were fed a high-fat atherogenic diet for 44 months and then a low-fat regression diet for 8 months. Serum total cholesterol decreased from 417+/-44 to 68+/-6 mg/dL (mean+/-SEM) and LDL cholesterol decreased from 375+/-44 to 27+/-5 mg/dL after the regression diet. In response to infusion of thrombin, the activated partial thromboplastin time (APTT) increased by 11+/-3 seconds before the regression diet and by 41+/-22 seconds after the regression diet (P=0.01). The peak level of circulating plasma APC was 52+/-9 ng/mL before the regression diet and 88+/-17 ng/mL after the regression diet (P=0.01). The APC sensitivity of plasma factor V was identical before and after the regression diet. Three additional atherosclerotic monkeys that remained on the high-fat diet for 8 months demonstrated no change in APTT or activation of protein C in response to thrombin. Short-term dietary regression of atherosclerosis produces enhanced anticoagulant responses to thrombin in vivo.

Regression of atherosclerosis in monkeys reduces vascular superoxide levels.

Superoxide (O2*-) in arteries may contribute to atherosclerosis in part by inactivation of nitric oxide. We hypothesized that regression of atherosclerosis in nonhuman primates is associated with a decrease in vascular NAD(P)H oxidase, decreased O2*- levels, and improved endothelium-dependent relaxation. Cynomolgus monkeys (n=28) were fed an atherogenic diet for 47+/-10 (mean+/-SE) months. In carotid arteries (containing advanced lesions), femoral arteries (moderate lesions), and saphena arteries (minimal lesions), we examined O2*- levels and vasomotor function. Compared with vessels from normal monkeys (n=8), O2*- levels (measured by lucigenin-enhanced chemiluminescence) were 3.3-fold higher in carotid, 1.7-fold higher in femoral, and not different in saphena arteries from atherosclerotic monkeys. Dihydroethidium staining also demonstrated increased O2*- levels throughout the vessel wall in femoral and carotid arteries from atherosclerotic monkeys. Components of the NAD(P)H oxidase (p22(phox) and p47(phox)) were increased in atherosclerotic arteries, and immunohistochemistry demonstrated colocalization primarily to areas of macrophage infiltration. Relaxation to acetylcholine was impaired in carotid and femoral, but not saphena, arteries from atherosclerotic monkeys. After 8 months of regression diet (n=9), serum cholesterol decreased to normal, and O2*- levels (basal and NAD(P)H-stimulated), as well as expression of NAD(P)H oxidase, returned toward normal. Relaxation to acetylcholine improved in femoral arteries, but not in the more diseased carotid arteries. We conclude that, in a primate model of moderately severe atherosclerosis and regression of atherosclerosis, changes in endothelial function are inversely related to O2*- and NAD(P)H oxidase levels. Reduction in vascular O2*- during regression of atherosclerosis may contribute to improvement in vasomotor function.

Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy.

Recent studies provide clear and convincing evidence that psychosocial factors contribute significantly to the pathogenesis and expression of coronary artery disease (CAD). This evidence is composed largely of data relating CAD risk to 5 specific psychosocial domains: (1) depression, (2) anxiety, (3) personality factors and character traits, (4) social isolation, and (5) chronic life stress. Pathophysiological mechanisms underlying the relationship between these entities and CAD can be divided into behavioral mechanisms, whereby psychosocial conditions contribute to a higher frequency of adverse health behaviors, such as poor diet and smoking, and direct pathophysiological mechanisms, such as neuroendocrine and platelet activation. An extensive body of evidence from animal models (especially the cynomolgus monkey, Macaca fascicularis) reveals that chronic psychosocial stress can lead, probably via a mechanism involving excessive sympathetic nervous system activation, to exacerbation of coronary artery atherosclerosis as well as to transient endothelial dysfunction and even necrosis. Evidence from monkeys also indicates that psychosocial stress reliably induces ovarian dysfunction, hypercortisolemia, and excessive adrenergic activation in premenopausal females, leading to accelerated atherosclerosis. Also reviewed are data relating CAD to acute stress and individual differences in sympathetic nervous system responsivity. New technologies and research from animal models demonstrate that acute stress triggers myocardial ischemia, promotes arrhythmogenesis, stimulates platelet function, and increases blood viscosity through hemoconcentration. In the presence of underlying atherosclerosis (eg, in CAD patients), acute stress also causes coronary vasoconstriction. Recent data indicate that the foregoing effects result, at least in part, from the endothelial dysfunction and injury induced by acute stress. Hyperresponsivity of the sympathetic nervous system, manifested by exaggerated heart rate and blood pressure responses to psychological stimuli, is an intrinsic characteristic among some individuals. Current data link sympathetic nervous system hyperresponsivity to accelerated development of carotid atherosclerosis in human subjects and to exacerbated coronary and carotid atherosclerosis in monkeys. Thus far, intervention trials designed to reduce psychosocial stress have been limited in size and number. Specific suggestions to improve the assessment of behavioral interventions include more complete delineation of the physiological mechanisms by which such interventions might work; increased use of new, more convenient "alternative" end points for behavioral intervention trials; development of specifically targeted behavioral interventions (based on profiling of patient factors); and evaluation of previously developed models of predicting behavioral change. The importance of maximizing the efficacy of behavioral interventions is underscored by the recognition that psychosocial stresses tend to cluster together. When they do so, the resultant risk for cardiac events is often substantially elevated, equaling that associated with previously established risk factors for CAD, such as hypertension and hypercholesterolemia.

Review of preclinical data of calcium channel blockers and atherosclerosis.

A variety of animal models have been used to determine whether calcium channel blockers exert an inhibitory effect on atherosclerotic lesion formation. These models include the cholesterol-fed rabbit, in which the lesions resemble the fatty-streak stage of atherosclerotic lesion development in humans. Diet-induced atherosclerosis in monkeys is also used and, in this case, the lesions resemble those found in humans, both in pathology and distribution. Other models involve mechanical injury superimposed on cholesterol feeding. Cellular and subcellular preparations are being used to investigate the mechanisms involved in the antiatherosclerotic activity of the calcium channel blockers. The ability of calcium channel blockers to slow atherosclerotic lesion formation is a class effect that is independent of their blood pressure-lowering effect, and occurs without any significant change in the plasma lipid profile. It is accompanied by a reduction in vessel wall cholesterol and calcium and is maintained over prolonged periods of treatment. The mechanisms that may be involved include inhibition of smooth muscle cell proliferation and migration, slowed platelet aggregation, restructuring of cholesterol-enriched cell membranes, enhanced gene expression for low-density lipoprotein receptor protein, inhibition of growth factor release, slowed calcium uptake, and restoration of endothelium-dependent relaxation.

Psychosocial stress causes endothelial injury in cynomolgus monkeys via β1-adrenoceptor activation

Current evidence links psychosocial factors to exacerbation of diet-induced atherosclerosis in monkeys via activation of the sympathetic nervous system. However, it is uncertain whether these factors can potentiate initial lesion formation, and do so even in the absence of dietary provocation, and whether any such effects can be prevented by beta-adrenergic blockade. As endothelial injury has been considered an initiating event in atherogenesis, we studied the effect of psychosocial stress on endothelial integrity in 48 adult male cynomolgus monkeys ( Macaca fascicularis). All animals were housed in 12 social groups of four monkeys each for 11 weeks. The monkeys in half of the groups were exposed to a socially unstable (`stressed') condition for 72 h and received saline ( n=8), a lipophilic β 1-blocker (metoprolol, 0.30 mg/kg per h; n=8), or hydrophillic β 1-blocker (atenolol, 0.15 mg/kg per h; n=8). The remaining six social groups were assigned to the socially stable (non-stressed) condition; for 72 h these animals all remained in their social groups and were similarly treated with saline ( n=8), metoprolol ( n=8), or atenolol ( n=8). The frequency of IgG-positive (injured) endothelial cells was estimated on en face (Häutchen) preparations from the thoracic aorta and coronary arteries. Psychosocial stress caused a significant increase in the number of injured endothelial cells in the circumostial areas of the descending thoracic aorta in the placebo group (0.3 vs. 0.8%, P<0.02), an effect that had not been demonstrated previously. Moreover, β-blockade significantly ( P<0.01) inhibited the stress effect, with no differences between the two beta-blocking agents. The number of injured endothelial cells in the non-branched portions of the aorta and coronary arteries were low and indistinguishable among groups; irregularities in the size and location of branching points in the coronary arteries precluded analysis of these sites. This study demonstrated that psychosocial stress induces endothelial injury, and that this effect is mediated via β 1-adrenoceptor activation.

Dietary soy protein and estrogen replacement therapy improve cardiovascular risk factors and decrease aortic cholesteryl ester content in ovariectomized cynomolgus monkeys

Estrogen replacement therapy (ERT) decreases the progression of coronary artery atherosclerosis in monkeys. Dietary soy protein also retards the progression of atherosclerosis relative to animal proteins such as casein. Soy protein contains weakly estrogenic compounds called isoflavones or phytoestrogens that may be responsible for the cardioprotective effects. This study was designed as a 2 × 2 factorial to determine the magnitude of soy protein's effects on cardiovascular risk factors relative to casein and lactalbumin, with or without estradiol treatment. Ovariectomized female monkeys were randomized to four treatment groups based on past dietary cholesterol consumption, their origin, and past reproductive history, and studied for 7 months. The animals were divided into (1) a group fed casein and lactalbumin as the protein source (n = 14), (2) a group fed casein and lactalbumin as the protein source plus 17β-estradiol (E2) (n = 13), (3) a group fed soybean protein isolate as the protein source (n = 11), and (4) a group fed soybean protein isolate as the protein source plus E2 (n = 10). Soy protein compared with casein consumption resulted in a significant improvement in plasma lipid and lipoprotein concentrations, a significant improvement in insulin sensitivity and glucose effectiveness as determined by minimal-model analyses, and a decrease in arterial lipid peroxidation. E2-treated monkeys had a significant reduction in fasting insulin levels and insulin to glucose ratios, total body weight, and amounts of abdominal fat, and had smaller low-density lipoprotein (LDL) particles. In addition, E2 treatment resulted in a significant reduction ( P = .001) in aortic cholesteryl ester content. A similar trend ( P = .14) was found for soy protein compared with casein. There also was a significant interaction ( P = .02) with soy and E2, such that animals consuming soy protein + E2 had the least arterial cholesteryl ester content. These results suggest that both ERT and dietary soybean protein have beneficial effects on cardiovascular risk factors. Interestingly, the two treatments affected different risk factors and together resulted in the greatest reduction in arterial cholesterol content. Further studies are needed to determine the active component of the soy protein and to assess its long-term effects on the cardiovascular system and other organ systems (such as the bones and reproductive system).

Effects of short-term hormone replacement therapies on low-density lipoprotein metabolism in cynomologus monkeys.

Estrogen replacement therapy reduces the risk of coronary heart disease in women and decreases the extent of atherosclerosis in monkeys. In our previous studies, estrogen treatment decreased arterial LDL degradation and accumulation, thus indicating one mechanism by which estrogen inhibits the progression of atherosclerosis. The influence of progestins on these processes remains nuclear. The objective of this study was to determine the effects of oral estrogen (conjugated equine estrogens) and progestin (medroxyprogesterone acetate) alone or in combination on arterial LDL metabolism after 12 weeks of atherogenic stimulus. This relatively short period of treatment was chosen to determine effects on arterial LDL metabolism before substantial subendothelial macrophage accumulation. In contrast to previous studies (16 to 18 weeks of treatment), when macrophages were present in the intima, neither estrogen nor progestin (nor their combination) had any effect on any index of arterial LDL metabolism. These results suggest that estrogen may preferentially reduce LDL metabolism in macrophages with little effect on cells of the normal artery. In contrast to arterial LDL metabolism, hepatic LDL uptake was significantly increased in animals treated with estrogen or estrogen plus progestin. Despite the increased LDL uptake by the liver, hepatic lipid content was significantly decreased by approximately 50% in both estrogen and estrogen-plus-progestin treatment compared with control and progestin-treated animals. The decrease in hepatic cholesterol content in hypothesized to be due to increased biliary secretion of cholesterol.

Tamoxifen inhibits arterial accumulation of LDL degradation products and progression of coronary artery atherosclerosis in monkeys.

Estrogen replacement therapy reduces the risk of coronary heart disease in postmenopausal women and inhibits progression of coronary artery atherosclerosis in monkeys. Tamoxifen is a nonsteroidal compound with mixed estrogen agonist and antagonist properties. Its antagonist activity is useful in chemotherapy of breast cancer and may have protective effects on plasma lipid concentrations, but its effects on atherogenesis have not been defined. The goal of this study was to examine the effect of tamoxifen on plasma lipids, arterial and hepatic LDL metabolism, and progression of coronary artery atherosclerosis in surgically postmenopausal female monkeys. Thirty-five monkeys were fed an atherogenic diet containing 1.3 mg.kg-1.d-1 tamoxifen (equivalent to the usual dose of 20 mg/d given to women). Thirty-one monkeys were fed the same atherogenic diet with no tamoxifen. Ten monkeys from each treatment group were fed the test diets for 12 weeks to examine the short-term effects of tamoxifen on arterial LDL metabolism. The rest of the monkeys were fed the test diets for 3 years to study the long-term effects of tamoxifen on development of atherosclerosis. In the short term, tamoxifen inhibited the rate of arterial accumulation of LDL degradation products overall (P = .03) and decreased hepatic cholesterol content (P = .003). In the long term, tamoxifen increased plasma concentrations of triglycerides (0.60 +/- 0.67 versus 0.23 +/- 0.02 mmol/L, P = .001) and reduced average LDL molecular weight (5.3 +/- 0.2 versus 4.8 +/- 0.1 g/mumol, P = 0.004) but had no effects on plasma total, LDL, or HDL cholesterol concentrations. Coronary artery atherosclerosis (intimal area, mean +/- SEM) was 0.25 +/- 0.06 mm2 in control monkeys and 0.12 +/- 0.03 mm2 in tamoxifen-treated monkeys (P = .057). We conclude that tamoxifen has antiatherogenic effects that may be modulated in part through direct effects on arterial LDL metabolism.

Dietary polyunsaturated fat decreases interaction between low density lipoproteins and arterial proteoglycans

Polyunsaturated dietary fat (n-3 and n-6) results in less atherosclerosis in monkeys compared to lard (Parks, J.S., Kaduck-Sawyer, J., Bullock, B.C., and Rudel, L.L., Arteriosclerosis 10, 1102-1112; Rudel, L.L., Parks, J.S., Johnson, F.L., and Babiak, J., J. Lipid Res. 27, 465-474, 1986). We hypothesized that this was due, in part, to a decreased reactivity of low density lipoproteins (LDL) with arterial proteoglycans (PG). To test this hypothesis, cynomolgus monkeys were fed diets containing lard, safflower oil (n-6 polyunsaturated; Poly), menhanden fish oil (FO), or oleic acid-rich safflower oil (oleinate; Mono) for 14 mon, and plasma LDL were isolated and characterized. Several properties of LDL thought to be important in the interaction of LDL with arterial PG were measured including LDL particle size, chemical composition, sialic acid content, density distribution, apolipoprotein E (apoE) content and cholesteryl ester transition temperature. Plasma LDL cholesterol concentrations (mg/dL) after 14 mon of diet consumption averaged (mean +/- SEM): FO (366 +/- 45), Lard (352 +/- 27), Poly (279 +/- 24), and Mono (230 +/- 43). The composition of LDL was similar among diet groups except that FO LDL were relatively depleted of cholesteryl ester and enriched in protein and were smaller in size. LDL sialic acid content was similar among diet groups (4.5-5.0 micrograms/mg LDL protein). The LDL apoE/B molar ratio, a measure of the apoE content per LDL particle averaged: Mono (3.0 +/- 1.0), Poly (2.0 +/- 0.1), Lard (1.8 +/- 0.5), and FO (1.0 +/- 0.2).(ABSTRACT TRUNCATED AT 250 WORDS)

Anatomic correlates of aortic pulse wave velocity and carotid artery elasticity during atherosclerosis progression and regression in monkeys.

We noninvasively measured changes in average aortic stiffness in 79 cynomolgus monkeys being fed cholesterol progression, regression, and control diets by measuring pulse wave velocity (PWV) in 260 experiments during a 30-month period. Every 6 months, a group of monkeys was studied with invasive aortic PWV techniques and with ultrasonically determined pressure-strain elastic modulus (Ep) of the carotid artery, and then the group was killed so that morphometric evaluation of atherosclerosis severity could be made. After 6 months of a cholesterol progression diet, PWV decreased slightly from 6.2 +/- 0.1 to 5.7 +/- 0.1 m/sec, followed by an approximate linear increase to 8.8 +/- 1.2 m/sec after 30 months on the diet. The corresponding ratio of intimal (plaque) area to medial area (IA/MA) measured on perfusion-fixed cross-sections of the abdominal and thoracic aortas increased from 0.16 +/- 0.07 at 6 months to 1.23 +/- 0.22 at 30 months. Monkeys in the regression groups were fed the cholesterol progression diet for 18 months, followed by a chow diet for 6 or 12 months. In the first 6 months of the cholesterol regression diet, PWV continued to increase from 7.0 +/- 0.2 to 8.1 +/- 0.4 m/sec, and IA/MA was 1.24 +/- 0.18. However, after 12 months of the cholesterol regression diet, PWV decreased to 6.8 +/- 0.4 m/sec, and IA/MA was 0.90 +/- 0.18. The variability of the data demonstrates that PWV is not a simple function of atherosclerosis severity, and the best simple correlation was r = 0.69 (r2 = 0.48) between PWV and intimal area. However, multiple regression analysis of aortic PWV, systolic (SP) and diastolic (DP) blood pressures, and total plasma cholesterol concentration (TPC), all of which can be measured with minimally invasive techniques, improved the prediction of the IA/MA ratio through the following equation: IA/MA = 0.127 PWV-0.039 DP+0.023SP+0.0003TPC-0.292 (r = 0.81, r2 = 0.66). These data suggest that arterial stiffness in combination with minimally invasive parameters can be used to predict the severity of diffuse asymptomatic atherosclerosis in monkeys. However, more widespread application of these data to humans is uncertain because of biological variability and differences between animal models and human subjects.

Fish oil decreases hepatic cholesteryl ester secretion but not apoB secretion in African green monkeys.

Two groups of African green monkeys were fed diets containing 40% of calories as fat with half of the fat calories as either fish oil or lard. The fish oil-fed animals had lower cholesterol concentrations in blood plasma (33%) and low density lipoproteins (LDL) (34%) than did animals fed lard. Size and cholesteryl ester (CE) content of LDL, strong predictors of coronary artery atherosclerosis in monkeys, were significantly less for the fish oil-fed animals although the apoB and LDL particle concentrations in plasma were similar for both diet groups. We hypothesized that decreased hepatic CE secretion led to the smaller size and reduced CE content of LDL in the fish oil-fed animals. Hepatic CE secretion was studied using recirculating perfusion of monkey livers that were infused during perfusion with fatty acids (85% 18:1 and 15% n-3) at a rate of 0.1 mumol/min per g liver. The rate of cholesterol secretion was less (P = 0.055) for the livers of fish oil versus lard-fed animals (3.3 +/- 0.5 vs. 6.0 +/- 1.2 mg/h per 100 g, mean +/- SEM) but the rate of apoB secretion was similar for both groups (0.92 +/- 0.15 vs. 1.01 +/- 0.13 mg/h per 100 g, respectively). The hepatic triglyceride secretion rate was also less (P less than 0.05) for the fish oil-fed animals (8.3 +/- 2.5 vs. 18.3 +/- 4.4 mg/h per 100 g). Liver CE content was lower (P less than 0.006) in fish oil-fed animals (4.1 +/- 0.8 vs. 7.4 +/- 0.7 mg/g) and this was reflected in a lower (P less than 0.04) esterified to total cholesterol ratio of perfusate VLDL (0.21 +/- 0.045 vs. 0.41 +/- 0.06). The hepatic VLDL of animals fed fish oil had 40-50% lower ratios of triglyceride to protein and total cholesterol to protein. From these data we conclude that livers from monkeys fed fish oil secreted similar numbers of VLDL particles as those of lard-fed animals although the hepatic VLDL of fish oil-fed animals were smaller in size and relatively enriched in surface material and depleted of core constituents. Positive correlations between plasma LDL size and both hepatic CE content (r = 0.87) and hepatic VLDL cholesterol secretion rate (r = 0.84) were also found.(ABSTRACT TRUNCATED AT 400 WORDS)