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Ultrastructural observations on the beneficial effects of polyunsaturated fatty acids (EPA and HDA) (Omega-3) on the aortic wall in cholesterol-fed rabbits
Abstract
The effects of a cholesterol-rich diet and linolenate-derived polyunsaturated fatty acids (Omega-3; EPA and HDA) supplementation on the aortic ultrastructure and serum lipid profiles (total cholesterol, HDL-cholesterol, and LDL-cholesterol) were investigated in rabbits. Three groups were established as follows: Group 1 (control) rabbits received regular diet (n=8), Group 2 received regular diet enriched with cholesterol for 12 months (n=14), and Group 3 received regular diet enriched with cholesterol for 4 months, then replaced by Max-EPA supplementation in the remaining 8 months (n=14). Crater-like openings on the endothelial cells and the presence of lipid vacuoles in cholesterol-fed rabbits (Group 2) suggest a very rapid uptake of circulating plasma lipids from the aortic lumen. In Group 3, the ultrastructure of the endothelial cells was almost normal and no lipid vacuoles were noted. Lipids stored in the subendothelial and adventitial regions of the vessel were noted. Biochemical findings were in accordance with the ultrastructural findings in Groups 2 and 3. It is possible that, in the cholesterol-fed, EPA, and HDA-replaced rabbits, endothelial cells may stop or reduce lipid uptake from the lumen and/or the rate of transport of lipid particles may increase. In other words, the behavior of the endothelial cells might be altered by the polyunsaturated fatty acids, as well as their circulating lipid-lowering action.
... Our results related to TT extract treatment also provide further experimental support for the indication of TT as an antilipidemic medical plant with some protective effects. In previous studies, it was evident that a highcholesterol diet caused ruptures in the vascular endothelium and enlargement of subendothelial lipid filled pinocytic vacuoles which normally exist intracellularly in small amounts (Demiroglu et al., 1991Demiroglu et al., , 1997). These structural alterations are consistent with our TEM and SEM results. ...
... However, subendothelial foam cells, collagen deposition in the tunica intima and tunica media layers, and electron-dense bodies were still present, suggesting a limited repair ability of TT. Our results related to the disappearance of endothelial rupture, which is a reaction to facilitate lipid transport from lumen to subendothelial region, and persistence of subendothelial vacuoles, are consistent with previous reports (Demiroglu et al., 1997). Endothelial dysfunction due to hyperlipidemia enhances endothelial permeability and leads to lipid collection in the subendothelial area. ...
The aim of this study was to investigate the pleotropic effects of an extract of a traditional herb, Tribulus terrestris (TT), on the lipid profile and vascular endothelium of the abdominal aorta in New Zealand rabbits fed a cholesterol-rich diet. Eighteen rabbits were randomly divided into three groups (n=6 for each). One experimental group (EG-I) was given a cholesterol-rich diet, a second experimental group (EG-II) was treated with TT following a cholesterol-rich diet, and a control group (CG) was fed a standard diet. Blood samples were collected on day 0 and then at weeks 4 and 12 to determine total serum cholesterol (TC), high density lipid-cholesterol (HDL-C), low density lipid-cholesterol (LDL-C) and triglyceride (TG) levels. Tissues were collected from the abdominal aorta for immunohistochemistry and transmission and scanning electron microscopy. In EG-II, the serum lipid profile was significantly lower than that of EG-I at week 12 with a reduction of TC: 65%; LDL-C: 66%; HDL-C: 64%; TG: 55%. Ultrastructural analysis revealed that endothelial damage was more prominent in EG-I compared to EG-II. The ruptured endothelial linings and damaged cellular surfaces increased in EG-I compared to EG-II. Our data indicate that dietary intake of TT can significantly lower serum lipid profiles, decrease endothelial cellular surface damage and rupture and may partially repair the endothelial dysfunction resulting from hyperlipidemia.
The plasma lipid and lipoprotein pattern has been examined in 130 Greenlandic west coast Eskimos with a life pattern, and especially with dietary habits, rather close to those of original Eskimos and essentially different from those of West Europeans. The age groups of the persons examined were chosen so as to be comparable with the age groups in which ischaemic heart disease prevails in West Europeans. The results of determination of plasma lipid and lipoproteins in the 130 Greenlandic west coast Eskimos, 69 women and 61 men, were compared with those of a similar examination in Denmark, including 25 female Eskimos living in Denmark. Significantly lower concentrations of total lipids, cholesterol, triglycerides, β-lipoproteins and pre-β-lipoproteins were found in Eskimos compared with Danish controls. The study on the Eskimos living in Denmark revealed plasma lipid values significantly higher than in Eskimos in Greenland and equal to those of Danish controls. This points strongly against a genetic and towards an environmental cause of the low lipid and lipoprotein concentrations in Greenlandic Eskimos. As in other societies with low plasma lipid concentrations, coronary atherosclerosis is rare among Greenlandic Eskimos. The Eskimos have low plasma lipid concentrations in spite of a high dietary intake of fat. This could be explained by the special composition of the Eskimo diet, with low content of saturated and high content of unsaturated fatty acids. Besides coronary atherosclerosis, diabetes mellitus is very rare among Eskimos. A correlation of this to the very low concentration of plasma triglycerides and pre-β-lipoproteins is tempting, but purely speculative.
We examined the effect of ethyl all-cis-5,8,11,14,17-icosapentaenoate (EPA-E) with high purity on circulating lipids in rats under several experimental conditions. In normolipidemic rats, EPA-E decreased the lipids in a dose-dependent manner. Clofibrate (100 mg/kg/day) was more potent in lowering the lipids than EPA-E (1000 mg/kg/day). In high cholesterol diet-fed rats, EPA-E (300 mg/kg/day) decreased the total cholesterol. However, clofibrate (300 mg/kg/day) had little effect on the total cholesterol. In hypertriglycemic rats induced by corn oil, EPA-E (300 mg/kg/day) or clofibrate (100 mg/kg/day) reduced the rise of triglycerides. EPA-E (300 mg/kg/day), clinofibrate (100 mg/kg/day) or clofibrate (300 mg/kg/day) caused a significant reduction in the lipids induced by the injection of Triton WR-1339. Furthermore, EPA-E (300 mg/kg/day) or clinofibrate (100 mg/kg/day) decreased the elevation of lipids produced by feeding the rats a casein-rich diet. These results show that EPA-E possesses potent inhibitory activity on experimental hyperlipidemia induced either exogenously or endogenously.
We found that rat peritoneal macrophages bind acetyl low density lipoprotein (AcLDL) by a saturable and specific manner and accumulate a substantial amount of cholesteryl ester (CE) when incubated with AcLDL. In macrophages enriched with eicosapentaenoic acid (EPA) by the ingestion of highly purified eicosapentaenoic acid-ethyl ester (EPA-E), the accumulation of CE was significantly decreased in a dose-dependent manner. In addition, the contents of EPA and docosapentaenoic acid (DPA) in macrophage phospholipids were dose dependently and significantly increased by EPA-E feeding. In contrast, the contents of arachidonic acid (AA) and docosahexaenoic acid (DHA) were unchanged. Furthermore EPA-E ingestion significantly decreased the Bmax of the AcLDL receptor without affecting the Kd in rat peritoneal macrophages. In addition, specific proteolytic degradation of AcLDL was also dose dependently inhibited by EPA-E feeding, indicating that the number of AcLDL receptor was significantly decreased after EPA-E ingestion. These findings indicate that EPA-E feeding inhibited CE accumulation mainly by decreasing the AcLDL receptors in macrophages. We speculate that EPA inhibits foam cell formation and this inhibitory effect may partly account for its anti-atherogenic action.
The effects of n-3 fatty-acid supplementation on serum lipids, platelet aggregation, and the development of atherosclerotic lesions were studied in the cholesterol-fed rabbit. Serum total cholesterol and LDL cholesterol values were significantly reduced in comparison with those of the nonsupplemented cholesterol-fed group (p less than 0.005, p less than 0.0025, respectively), though still higher than those of the control group (p less than 0.0025, p less than 0.0125 respectively). Platelet aggregation was reduced below that of the cholesterol-fed and the control levels (p less than 0.0005, p less than 0.0025, respectively). The endothelial injury encountered in cholesterol-fed rabbits was inhibited in the supplemented group. It is concluded that n-3 fatty acids suppress atherogenesis in this animal model by interfering with platelet aggregation and lipid metabolism.
We examined the relation between the serum total cholesterol level and the risk of death from stroke during six years of follow-up in 350,977 men, 35 to 57 years of age, who had no history of heart attack and were not currently being treated for diabetes mellitus. The diagnosis of stroke and the type of stroke were obtained from death certificates. Using proportional-hazards regression to control for age, cigarette smoking, diastolic blood pressure, and race or ethnic group, we found that the six-year risk of death from intracranial hemorrhage (International Classification of Diseases, ninth edition [ICD-9], categories 431 and 432) was three times higher in men with serum cholesterol levels under 4.14 mmol per liter (160 mg per deciliter) than in those with higher cholesterol levels (P = 0.05 by omnibus test across five cholesterol levels). On the other hand, a positive association was observed between the serum cholesterol level and death from nonhemorrhagic stroke (P = 0.007). The inverse association of the serum cholesterol level with the risk of death from intracranial hemorrhage was confined to men with diastolic blood pressure greater than or equal to 90 mm Hg, in whom death from intracranial hemorrhage is relatively common. We conclude that there is an inverse relation between the serum cholesterol level and the risk of death from hemorrhagic stroke in middle-aged American men, but that its public health impact is overwhelmed by the positive association of higher serum cholesterol levels with death from nonhemorrhagic stroke and total cardiovascular disease (ICD-9 categories 390 through 459).
CARDIOVASCULAR disease remains the chief cause of death in the United States and Western Europe, and atherosclerosis, the principal cause of myocardial and cerebral infarction, accounts for the majority of these deaths.1 This review, like its predecessor,2 will not attempt to cover all literature on atherosclerosis. In a previous review of the pathogenesis of atherosclerosis,2 Glomset and I discussed various hypotheses of atherogenesis2 3 4 5 6 7 and emphasized the importance of intimal smooth-muscle proliferation as the key event in the development of the advanced lesions of atherosclerosis. The response-to-injury hypothesis of atherogenesis2 3 4 5 6 proposes that "injury" to the endothelium is the initiating event in . . .
We investigated the influence of fish oil on cholesterol induced atherosclerosis in rabbits. Group I, a control group was fed a cholesterol-free diet, group II was fed a diet supplemented with 1.5% cholesterol, group III received in addition to cholesterol supplementation a purified fish oil concentrate (Maxepa, 2 ml/d). The animals received these diets for 5 months (100 g/d). Aortic atherosclerosis as measured by planimetry of sudanophilic lesions was significantly higher (+59%) in group III as compared with group II, even though serum cholesterol levels were comparable. No differences were found in platelet half-life times between groups II and III, but these values were significantly lower than the half-life of platelets in the control group I. Total serum peroxide levels, expressed as malondialdehyde equivalents were significantly elevated in the fish oil-treated group. This may be due to malondialdehyde modification of the lipoproteins and may be responsible for the enhanced development of atherosclerosis in these animals.
The low death rate from coronary heart disease among the Greenland Eskimos has been ascribed to their high fish consumption. We therefore decided to investigate the relation between fish consumption and coronary heart disease in a group of men in the town of Zutphen, the Netherlands. Information about the fish consumption of 852 middle-aged men without coronary heart disease was collected in 1960 by a careful dietary history obtained from the participants and their wives. During 20 years of follow-up 78 men died from coronary heart disease. An inverse dose-response relation was observed between fish consumption in 1960 and death from coronary heart disease during 20 years of follow-up. This relation persisted after multiple logistic-regression analyses. Mortality from coronary heart disease was more than 50 per cent lower among those who consumed at least 30 g of fish per day than among those who did not eat fish. We conclude that the consumption of as little as one or two fish dishes per week may be of preventive value in relation to coronary heart disease.
The proportions of fatty acids in lipids of subcutaneous adipose tissue was compared in closely age-matched, urban men from two populations with a great difference in mortality from arteriosclerosis, namely in 50 Americans and 56 Japanese aged 15-65 yr who had died suddenly and unexpectedly. Specimens from both groups were analyzed side by side for fatty acids by gas-liquid chromatography. Compared with Japanese, Americans had significantly (P<0.01) higher proportions of lauric (+ 0.2%), myristic (+ 0.4%), palmitic (+ 1.4%), stearic (+ 2.2%), and oleic (+ 5.3%) and lesser of palmitoleic (- 1.8%), linoleic (-6.3%), and linolenic (-0.4%) acids. Japanese had higher proportions of longer chain polyunsaturated fatty acids. The distributions of fatty acids for the groups at ages 35-44 yr had significant differences. With age, Americans showed significant increases of palmitic and oleic acids and decreases of lauric, myristic, stearic, and linoleic acids; Japanese showed no correlations of proportions of fatty acids with age. The significant correlations between per cent standard body weight and fatty acids in Americans were positive for palmitic and negative for lauric and stearic acids, and in Japanese, negative for myristic acid. The patterns of interacid correlations were dissimilar for the groups. These patterns may be stable characteristics of these groups providing further insight into their fatty acid metabolism. The relationships with the fatty acid compositions of the American and Japanese diets are discussed.
An epidemiological survey of several chronic diseases in the Upernavik district, Northwest Greenland, is reported. The study population (approx. 1800 inhabitants) is one of the remaining whaling and sealing populations in Greenland. It was observed over the 25-year period 1950-74 as to the incidence of the diseases, which was based on all cases diagnosed in hospital during this period. The disease pattern of the Greenlanders differs from that of West-European populations, having a higher frequency of apoplexy and epilepsy but a lower frequency or absence of acute myocardial infarction, diabetes mellitus, thyrotoxicosis, bronchial asthma, multiple sclerosis and psoriasis. The distribution of cancer types differs from that of the Danish population, but the total incidence of cancer is of the same magnitude. Further comparable studies should be performed in Greenlandic districts that are characterized by more profound changes in life style, in order to elucidate the effect of these changes on the disease pattern.
Hypolipidemic effect of ethyl alt-cis 5EPA-E) in rats
- K Mizuguchi
- T Yano
- M Kojima
Mizuguchi K, Yano T, Kojima M, et al. (1992) Hypolipidemic effect of ethyl alt-cis 5,8,t 1,14,17-eicosapentaenoate (EPA-E) in rats. Jpn J Pharmacol (Japan) 59:307-312.
- H O Bang
- J Dyerberg
- A B Nieisen
- HO Bang
Fish consumption and mortality from coronary heart disease
- S E Norell
- A Ahlbom
- M Feychting
- SE Norell
Clinical applications of fish oils
- J Z Yetiv
- JZ Yetiv
Lipoprotein(a) in heart disease
- R M Lawn
- RM Lawn