Cholesterol-fed Rabbits Research Articles

The changes in the endothelial expression of cell adhesion molecules and iNOS in the vessel wall after the short-term administration of simvastatin in rabbit model of atherosclerosis

Cell adhesion molecules P-selectin, VCAM-1 and ICAM-1 play an important role in the pathogenesis of atherosclerosis. High levels of nitric oxide (NO) produced by inducible NO synthase (iNOS) have been associated with atherosclerotic processes. Simvastatin is an HMG-CoA reductase inhibitor responsible for many clinical benefits. The aim of this study was to detect and quantify changes in endothelial expression of P-selectin, VCAM-1, ICAM-1 and iNOS in the vessel wall after the shortterm administration of simvastatin in a rabbit model of atherosclerosis. Eighteen New Zealand White rabbits were randomly divided into three groups (n=6). In the cholesterol group, rabbits consumed an atherogenic diet (0.4% cholesterol) for eight weeks. In the simvastatin group, rabbits consumed an atherogenic diet for six weeks and then consumed an atherogenic diet supplemented with simvastatin (10 mg kg(-1)) for two weeks. Biochemical analysis showed that administration of simvastatin led to an almost two-fold lowering of the total serum cholesterol, VLDL, LDL and HDL, but not triglycerides, compared with the cholesterol-fed rabbits only. Stereological analysis of the immunohistochemical staining revealed that administration of simvastatin (10 mg kg(-1) daily) in an atherogenic diet decreased the endothelial expression of P-selectin, ICAM-1 and iNOS in both aortic arch and carotid artery compared with the cholesterol fed-rabbits only. We conclude that simvastatin has beneficial effects on endothelial function by decreasing expression of P-selectin, ICAM-1 and iNOS in endothelial cells in the very early stages of atherogenesis.

Hypolipidemic and Antioxidant Effects of Dandelion (Taraxacum officinale) Root and Leaf on Cholesterol-Fed Rabbits

Dandelion (Taraxacum officinale), an oriental herbal medicine, has been shown to favorably affect choleretic, antirheumatic and diuretin properties. Recent reports have indicated that excessive oxidative stress contributes to the development of atherosclerosis-linked metabolic syndrome. The objective of this current study was to investigate the possible hypolipidemic and antioxidative effects of dandelion root and leaf in rabbits fed with a high-cholesterol diet. A group of twenty eight male rabbits was divided into four subgroups; a normal diet group, a high-cholesterol diet group, a high-cholesterol diet with 1% (w/w) dandelion leaf group, and a high-cholesterol diet with 1% (w/w) dandelion root group. After the treatment period, the plasma antioxidant enzymes and lipid profiles were determined. Our results show that treatment with dandelion root and leaf positively changed plasma antioxidant enzyme activities and lipid profiles in cholesterol-fed rabbits, and thus may have potential hypolipidemic and antioxidant effects. Dandelion root and leaf could protect against oxidative stress linked atherosclerosis and decrease the atherogenic index.

Appropriate doses of Granulocyte-Colony Stimulating Factor Reduced Atherosclerotic Plaque Formation and Increased Plaque Stability in Cholesterol-Fed Rabbits

To evaluate the dose-response effects of granulocyte-colony stimulating factor (G-CSF) on atherosclerosis, we examined how G-CSF treatment at different concentrations affects atherosclerotic plaque formation in the aorta of cholesterol-fed rabbits. Japanese White rabbits (n=8 each) fed on a 1.5% cholesterol diet were subcutaneously injected with G-CSF at 50 (GL), 100 (GM), or 300 microg/kg/day (GH) for five days, or with 3 cycles of G-CSF at 100 microg/kg/day at 3-week intervals (GM3), or human serum albumin (Control). The extent and composition of atherosclerosis was evaluated 14 weeks after cholesterol feeding. Although G-CSF treatment did not affect plasma lipid levels, the percentage of aortic surface involvement in the GM3 group was significantly decreased (p<0.05) compared with the Control group. Histological analysis revealed that the intima media ratio was also diminished in GM and GM3 groups. The extent of intimal smooth muscle cell accumulation was higher in GL and GM3 groups than in the Control group. TIMP-2 mRNA expression in the aortic tissue was increased by G-CSF treatment. Our results suggest that appropriate doses of G-CSF reduced atherosclerotic plaque formation and increased plaque stability in cholesterol-fed rabbits.

Validated Sandwich ELISA for the Quantification of von Willebrand Factor in Rabbit Plasma

von Willebrand Factor (vWF) is a multimeric plasma protein important for platelet plug formation. As part of its haemostatic role, it is released from endothelial cells during vascular stress or injury and is considered an excellent biomarker of endothelial function. Currently, there are no validated kits available to measure vWF in rabbits. We developed a sensitive and reproducible sandwich enzyme-linked immunosorbent assay (ELISA) for detection of vWF in rabbit plasma using commercially available antibodies and reagents. Purified human vWF was used as a calibrator standard with a dynamic range of 1.56–100 ng/mL. The Minimum Required Dilution for rabbit plasma was 1:100. When plasma was spiked with 3.76 or 10 ng/mL vWF, recovery was 108 ± 2% and 93 ± 2%, respectively. Intra- and inter-assay precision for 8 rabbit plasma samples were 3% and 4%, respectively. The Minimum Detectable Concentration was 254 pg/mL for purified human vWF and 1:10,700 dilution of cholesterol-fed rabbit plasma, and the Reliable Detection Limits were 457 pg/mL and 1:5940. Three freeze-thaw cycles significantly decreased vWF concentrations for purified human vWF and 2 of 3 plasma samples assayed. This ELISA provides sensitive and reproducible measurements of rabbit plasma vWF, which is an important biomarker for cardiovascular research.

Effect of High Fat Diet Without Cholesterol Supplementation on Oxidative Stress and Lipid Peroxidation in New Zealand White Rabbits

Dietary fats may affect coronary artery disease risk by influencing factors other than serum cholesterol. The effect of diets containing coconut oil and sunflower oil without cholesterol supplementation on oxidative stress and lipid peroxidation were studied in male New Zealand White rabbits. Animals assigned to four groups (control, cholesterol-fed, coconut oil-fed and sunflower oil-fed), given an isocaloric diet and studied for 6 months. The lipid profile, reduced glutathione, glutathione peroxidase, superoxide dismutase, vitamin C and lipid peroxidation were evaluated at the beginning of the study, at the third month and at the end of the study period. Serum lipid values did not show significant variation between animals fed coconut oil and sunflower oil, but total cholesterol, triglycerides and LDL-cholesterol were significantly higher and HDL-cholesterol was reduced in cholesterol-fed animals. Lipid peroxidation was higher in cholesterol-fed and sunflower oil-fed rabbits compared to controls and coconut oil-fed rabbits. Though other parameters such as reduced glutathione, glutathione peroxidase, superoxide dismutase and ascorbate did not vary between the two oil-fed rabbit groups, cholesterol-fed rabbits showed severe oxidative stress. We conclude that in the absence of cholesterol supplementation, coconut oil intake up to 30% of daily energy supply did not cause hypercholesterolemia or oxidative stress in rabbits.

Early identification of aortic valve sclerosis using iron oxide enhanced MRI

To test the ability of MION-47 enhanced MRI to identify tissue macrophage infiltration in a rabbit model of aortic valve sclerosis (AVS). The aortic valves of control and cholesterol-fed New Zealand White rabbits were imaged in vivo pre- and 48 h post-intravenous administration of MION-47 using a 1.5 Tesla (T) MR clinical scanner and a CINE fSPGR sequence. MION-47 aortic valve cusps were imaged ex vivo on a 3.0T whole-body MR system with a custom gradient insert coil and a three-dimensional (3D) FIESTA sequence and compared with aortic valve cusps from control and cholesterol-fed contrast-free rabbits. Histopathological analysis was performed to determine the site of iron oxide uptake. MION-47 enhanced the visibility of both control and cholesterol-fed rabbit valves in in vivo images. Ex vivo image analysis confirmed the presence of significant signal voids in contrast-administered aortic valves. Signal voids were not observed in contrast-free valve cusps. In MION-47 administered rabbits, histopathological analysis revealed iron staining not only in fibrosal macrophages of cholesterol-fed valves but also in myofibroblasts from control and cholesterol-fed valves. Although iron oxide labeling of macrophage infiltration in AVS has the potential to detect the disease process early, a macrophage-specific iron compound rather than passive targeting may be required.

The diameter of liver sinusoidal fenestrae is not a major determinant of lipoprotein levels and atherosclerosis in cholesterol-fed rabbits

The liver is a key organ in lipid and lipoprotein metabolism. It has been postulated that a small diameter of sinusoidal fenestrae retards clearance of chylomicron remnants, resulting in hypercholesterolemia and atherosclerosis. However, this hypothesis has not been rigorously tested hitherto. In the current study, we compared plasma levels of proatherogenic lipoproteins and assessed the development of atherosclerosis at distinct locations throughout the arterial tree in heterozygous New Zealand White and Dutch Belt rabbits that are deficient in low-density lipoprotein receptor and with an average fenestrae size of 103 and 124 nm, respectively. Feeding of a 0.15% cholesterol diet for 4 months resulted in similar total plasma cholesterol levels in New Zealand White (420±20 mg/dl) and Dutch Belt (380±30 mg/dl) rabbits. Following isolation of lipoproteins by ultracentrifugation, no biologically significant differences in very-low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein cholesterol levels were observed between cholesterol-fed New Zealand White and Dutch Belt rabbits. Furthermore, the relative amount of intestinally derived apolipoprotein-B48-containing lipoproteins did not differ significantly between both strains (7.3±0.42% vs. 8.0±0.54%). Atherosclerosis was more pronounced in the thoracic aorta in New Zealand White rabbits than in Dutch Belt rabbits, but the reverse was observed with the abdominal aorta. These topographic differences cannot be explained by circulating lipoprotein levels. The data presented in this study do not support the hypothesis that the diameter of fenestrae is an important determinant of chylomicron remnant levels, diet-induced hypercholesterolemia, and atherosclerosis in cholesterol-fed rabbits.

Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis

Expression of ABCA1 is regulated by transcription of the gene and calpain-mediated proteolytic degradation, and inhibition ABCA1 degradation results in increased ABCA1 and HDL biogenesis in vitro. We examined whether this approach could be a potential antiatherogenic treatment. Although probucol inhibits both the activity and degradation of ABCA1, its oxidized products, spiroquinone and diphenoquinone, reduce degradation of ABCA1 without inhibiting its activity or altering transcription of the ABCA1 gene. Accordingly, both compounds enhanced apolipoprotein A-I/ABCA1-dependent generation of HDL in vitro, and increased hepatic ABCA1 and plasma HDL without increasing antioxidant activity in plasma when given to rabbits. Both compounds also decreased vascular lipid deposition in cholesterol-fed rabbits. We therefore conclude that stabilization of ABCA1 against calpain-mediated degradation is a novel and potentially important strategy to increase HDL formation and prevent atherosclerosis. Spiroquinone and diphenoquinone are potential seeds for development of such drugs.

Broad DNA repair responses in neural injury are associated with activation of the IL-6 pathway in cholesterol-fed rabbits.

The importance of DNA repair in the pathogenic mechanism of Alzheimer's Disease (AD) is still poorly understood. Here, we report that a broad range of responses by DNA repair proteins plays a critical role in the regulation of inflammatory response in rabbits fed with cholesterol-rich diet, a model system for AD. We found accumulation of oxodG DNA adduct in the brain of rabbits fed with cholesterol-enriched diets compared to control diets, which subsequently induced a broad range of DNA repair protein activities. Also, the hippocampus was identified as the primary site of oxidative DNA damage and elevated OGG1 activity. In addition, a physical interaction between XPB and OGG1 may account for a potential mechanism involving these DNA repair responses. DNA repair proteins also impact activation of various signaling cascades, including Src in response to cholesterol oxidation. Furthermore, OGG1 deficient mice showed no IL-6 activation as seen in wt mice but a drastic increase of TNF-alpha, a pro-inflammatory cytokine. Thus, OGG1 may be associated with cytokine production induced by high cholesterol levels, impacting neurodegeneration. Together, our studies suggest that critical DNA repair proteins are associated with development of AD, and may serve as potential targets for the treatment of AD.

The effects of ACE inhibitors and other antihypertensive drugs on cardiovascular risk factors and atherogenesis

The effects of antihypertensive therapy on the atherosclerotic process and differences among various treatment approaches have been studied in several animal models. Studies in cholesterol-fed rabbits have indicated that beta blockers and calcium antagonists can inhibit the development of aortic atherosclerosis induced by marked hypercholesterolemia. However, no such antiatherosclerotic action has been apparent with these agents in the Watanabe heritable hyperlipidemic (WHHL) rabbit. A study was conducted to determine the effects of the angiotensin-converting enzyme (ACE) inhibitor captopril administered orally for 9 months on the development of atherosclerosis in normotensive WHHL. Compared with controls, the treated animals had a significant reduction in atherosclerosis of the descending thoracic aorta. These effects were associated with significantly lower blood pressure, though within the normal range, in captopril-treated versus control animals. In the captopril group, the atherosclerotic plaques were thinner and less cellular than plaques of similar gross severity in control WHHL. The findings indicate that the ACE inhibitor captopril can inhibit atherogenesis in the WHHL, which has been resistant to such therapy with other antihypertensive drugs.

Extract from the leaf of nucifera reduced the development of atherosclerosis via inhibition of vascular smooth muscle cell proliferation and migration

Nelumbo nucifera GAERTN, a perennial aquatic plant, has been used as a medicinal herb in China and India. We have previously reported that consumption of nucifera leaf extract (NLE) reduced the development of atherosclerosis in cholesterol-fed rabbits; however, the molecular mechanisms involved were unclear. Atherosclerotic plaque is generated partly by proliferation and migration of vascular smooth muscle cells (VSMC). Herein, we demonstrated that VSMC treated with NLE-triggered apoptosis and affected the JNK and p38 Mitogen-Activated Protein Kinase (MAPK) pathways. Pre-treating VSMC with inhibitors of JNK, p38, and p53 reduced NLE-induced apoptosis. Non-cytotoxic doses of NLE also abolished secretion of MMP-2/9 and inhibited cell migration via restraining the FAK/PI 3-kinase/small G protein pathway. Histopathological examination showed that 1.0% of NLE reduced neointima formation conspicuously and inhibited smooth muscle cell proliferation and MMP-2 secretion in the blood vessel of rabbits fed with a high cholesterol diet (HCD). We also verified that the extract’s total phenolic acids and the total flavonoids were approximately about 70%. In conclusion, our results shed light on the molecular mechanisms whereby the polyphenol-rich water extract of nucifera leaves could inhibit both proliferation and migration of VSMC, and it might serve as a potential anti-atherogenic agent.

Effect of rapeseed oil-derived plant sterol and stanol esters on atherosclerosis parameters in cholesterol-challenged heterozygous Watanabe Heritable Hyperlipidaemic rabbits

Rapeseed oil (RSO) is a novel source of plant sterols, containing the unique brassicasterol in concentrations higher than allowed for plant sterol blends in food products in the European Union. Effects of RSO sterols and stanols on aortic atherosclerosis were studied in cholesterol-fed heterozygous Watanabe heritable hyperlipidaemic (Hh-WHHL) rabbits. Four groups (n 18 per group) received a cholesterol-added (2 g/kg) standard chow or this diet with added RSO stanol esters (17 g/kg), RSO stanol esters (34 g/kg) or RSO sterol esters (34 g/kg) for 18 weeks. Feeding RSO stanol esters increased plasma campestanol (P < 0.001) and sitostanol (P < 0.001) and aortic campestanol (P < 0.05) compared with controls. Feeding RSO sterol esters increased concentrations of plasma campesterol (P < 0.001), sitosterol (P < 0.001) and brassicasterol (P < 0.001) and aortic campesterol (P < 0.01). Significantly lower plasma cholesterol (P < 0.001) was recorded in the treated groups after 3 weeks and throughout the study. LDL-cholesterol was reduced 50 % in the high-dose RSO sterol ester (P < 0.01) and high-dose RSO stanol ester (P < 0.001) groups compared with controls. Atherosclerotic lesions were found in three rabbits in each of the RSO stanol ester groups and in one in the RSO sterol ester group. Aortic cholesterol was decreased in the treated groups (P < 0.001) in response to lowering of plasma cholesterol induced by RSO sterol and stanol esters. In conclusion, RSO stanol and sterol esters with a high concentration of brassicasterol were well tolerated. They were hypocholesterolaemic and inhibited experimental atherosclerosis in cholesterol-fed Hh-WHHL rabbits. A significant uptake of plant sterols into the blood and incorporation of campesterol and campestanol into aortic tissue was recorded.

Atherosclerosis regression study in rabbits upon olive pomace polar lipid extract administration

Background and aims Virgin olive oil polar lipid extract (OOPL) and olive pomace polar lipid extract (PPL) have similar antiatherosclerotic effects in cholesterol-fed rabbits. Our aim was to compare the effect of PPL with that of simvastatin on the progression of atherogenesis. Methods and results Rabbits were fed an atherogenic diet for 6 weeks in order to develop dyslipidemia and atheromatous lesions. Following documentation of these events in random animals (group A, n = 6), the remaining were fed for 3 weeks with: standard chow alone (group B, n = 6), chow supplemented with PPL (group C, n = 6), and chow supplemented with simvastatin (group D, n = 6). Blood was collected at 0, 6 and 9 weeks, to determine plasma lipid levels, plasma PAF-AH activity, platelet aggregation (PAF-EC 50), resistance of plasma to oxidation (RPO) and extent of atheromatous lesions in aortas. The atherogenic diet induced dyslipidemia and increased PAF-AH activity. Dyslipidemia and PAF-activity reduced more effectively in groups C and D. RPO decreased in group B only. PAF-EC 50 values decreased in group C only. Atherogenesis progression in group C was prevented to an extent indistinguishable from that in group D. PAF-AH activity was positively correlated, whereas RPO was negatively correlated with the extent of atheromatous lesions. Conclusion PPL, as a dietary supplement, is equipotent to simvastatin in preventing the progression of atherogenesis.

EP2300 Compounds: Focusing on the Antiatherosclerotic Properties of Squalene Synthase Inhibitors

Although treatment with statins significantly reduces adverse cardiovascular outcomes, several studies have shown that cardiovascular events continue to occur in two thirds of all patients. A logical pharmacologic approach to further reduce cardiovascular disease mortality should be focused on direct modifiers of atherosclerosis or lipid-modifying agents with different mechanism of action than existing drugs against dyslipidemia. Squalene synthase inhibitors can decrease circulating low-density lipoprotein (LDL)-cholesterol by an increased expression of hepatic LDL receptors in a similar manner to statins. Also, depending on their structure, they may possess antiatherosclerotic properties independent of their lipid-modifying effects. This review, following a brief introduction to different classes of squalene synthase inhibitors and representative molecules, presents the accumulating in vitro and in vivo experimental evidence relevant to squalene synthase inhibitors EP2306 and EP2302 and discusses their properties. EP2306 and EP2302 show a similar inhibitory effect in the progression of atherosclerosis in the cholesterol-fed rabbit. Moreover, EP2306 showed a significant long-term antiatherosclerotic effect not shared by simvastatin or their combination in this animal model. EP2302 also showed a favorable effect in the regression of pre-established atherosclerotic lesions. It is reasonable to hypothesize that EP2302, due to its NO-releasing and enhancing properties, could have additional advantages compared to EP2306. Treatment with EP2300 compounds did not adversely affect liver transaminases or cause toxicity on various organs of the cholesterol-fed rabbit. The satisfactory safety profile of EP2300 compounds in this animal model is a promising finding in view of future clinical studies.

Oral supplementation with l-aspartate and l-glutamate inhibits atherogenesis and fatty liver disease in cholesterol-fed rabbit

Previous studies have shown that dietary supplementation with L-aspartate and L-glutamate inhibits fatty streak initiation in cholesterol-fed rabbit. The present study investigates the role of dicarboxylic amino acids on the progression of fatty streaks and the development of fatty liver disease, which were caused in New Zealand White rabbits after a 0.5% w/w cholesterol diet for 7 weeks. A group of animals additionally received a combination of 12.5 mM L-aspartate and 12.5 mM L-glutamate per day through drinking water. Total cholesterol (TC), high-density lipoproteins cholesterol (HDLC), non-HDLC and triacylglycerol (TAG) concentrations were measured in plasma. Serum gamma-glutamyl transferase (gamma-GT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were also determined. At the end of dietary intervention, animals were sacrificed. Aortic, hepatic and brain lesions were evaluated after staining with hematoxylin and eosin. Supplementation with dicarboxylic amino acids inhibited the progression of aortic intima thickness (P < 0.05) and the development of liver lesions (P < 0.05). TC, non-HDLC and TAG were similarly increased in both cholesterol-fed groups. Serum gamma-GT and AST activities elevated during the study in all cholesterol-fed animals but the elevation of gamma-GT was milder and significantly lower in rabbits treated with L-aspartate and L-glutamate (P < 0.05). ALT activity was not affected by cholesterol feeding. In conclusion, oral supplementation with L-aspartate and L-glutamate inhibits the progression of atherogenesis and the development of fatty liver disease in the animal model of cholesterol-fed rabbit. The beneficial effects of dicarboxylic amino acids reflect the limited elevation of serum gamma-GT activity.

Nasal immunization with heat shock protein 65 attenuates atherosclerosis and reduces serum lipids in cholesterol-fed wild-type rabbits probably through different mechanisms

In recent years atherosclerosis has proved to be associated with microbial infection, inflammation and autoimmunity. Conservative heat shock protein (HSP) 65/60 is a major autoantigen of atherosclerosis. In the current study, experiments were specifically designed to investigate whether a nasal immunization with HSP65 could attenuate atherosclerosis in a cholesterol-fed wild-type animal model and explore its influence on serum lipids. Wild-type rabbits were nasally treated with HSP65 10 times on alternate days. At the end of the experiment, the rabbits showed remarkably lightened lesions in aortas. The suppression of T cell proliferation, increase of IL-10 production and absence of related antibodies implied that a tolerance to HSP65 was successfully established. Simultaneously, the serum lipid levels were down-regulated significantly in this group. Further results of another group immunized with conjugated protein HSP65+CTB-P277 showed that the lipid reduction could also be achieved by an immunization without inducing tolerance. But this simple reduction of lipids could not eventually alleviate atherosclerosis. In conclusion, nasal administration of HSP65 can effectively attenuate atherosclerosis in cholesterol-fed wild-type rabbits primarily by inducing an unresponsive state of tolerance. The accompanying reduction of lipids, which probably results from a different immune mechanism other than tolerance, cannot ultimately prevent the development of atherosclerotic lesions alone.

Atrial natriuretic peptide decreases aorta stiffness in cholesterol-fed anesthetized rabbits

Aortas from Watanabe heritable hyperlipidemic rabbits show in vitro impaired vasodilatory response to atrial natriuretic peptide (ANP) during atherosclerosis progression. To test a similar reaction in vivo, the effect of ANP administration on pulse wave velocity (PWV, index of aorta stiffness) was investigated in 10 normal and 10 cholesterol-fed (2% cholesterol-loaded feeding for 4 weeks) anesthetized male New Zealand White (NZW) rabbits. Invasively taken carotid and femoral blood pressures (BP) were recorded, simultaneously with ECG, and blood samples for ANP measurement (by RIA) were taken at 0 min and 20, 40, 60 min following an intravenous 20-min administration of either 0.2 μg kg −1 min −1 hANP in 5 ml normal saline or only 5 ml saline. Mild to moderate atherosclerosis was found in ascending aorta. BP decreased by ANP only at 20 min in both groups, whereas only in cholesterol-fed rabbits the borderline ( p = 0.09) increased at 0 min PWV was lowered ( p = 0.008) in all recording times. With any degree of increase of systolic BP (SBP) PWV increased less in ANP receivers. Atherosclerosis and SBP were the most important determinants of PWV and the effect of ANP was independent of confounding factors. It is concluded that short-term ANP administration in doses to achieve levels approximately threefold the pretreatment ones in normal and mildly to moderately atherosclerotic anesthetized NZW rabbits, causes an improvement of aorta stiffness only in atherosclerotic rabbits.

The thyromimetic T-0681 protects from atherosclerosis

This report describes studies in hyperlipidemic New Zealand White (NZW) rabbits investigating the impact of the liver-selective thyromimetic T-0681 on lipoprotein metabolism and the development of atherosclerosis. Prolonged treatment with T-0681 increased the hepatic expression of both LDL receptor and scavenger receptor class B, type I without affecting cholesteryl ester transfer protein activity. Upregulation of hepatic lipoprotein receptors was accompanied by a marked decrease of apolipoprotein B-containing lipoproteins, reflected by a 60% reduction of plasma cholesterol and a >70% reduction of plasma triglyceride levels. Most importantly, T-0681 reduced the development of atherosclerosis by 80% in NZW rabbits on high-cholesterol chow. Our data suggest that liver-selective thyromimetics, such as T-0681, may prove to be useful therapeutic agents against the development of atherosclerosis in humans.

Diphenyl Diselenide Decreases Serum Levels of Total Cholesterol and Tissue Oxidative Stress in Cholesterol-fed Rabbits

Hypercholesterolaemia and oxidative stress are well-known risk factors in coronary artery diseases. Diphenyl diselenide is a synthetic organoselenium compound that has been shown to have in vitro and in vivo antioxidant properties. In this study, we investigated whether diphenyl diselenide could reduce the hypercholesterolaemia and diminish the tissue oxidative stress in cholesterol-fed rabbits. Twenty-four New Zealand white male rabbits were randomly divided into four groups. Each group was fed a different diet as follows: Control group--regular chow; Cholesterol group--1% cholesterol-enriched diet; diphenyl diselenide group--regular diet supplemented with 10 ppm diphenyl diselenide; and Chol/diphenyl diselenide group--the same cholesterol-rich supplemented with 10 ppm diphenyl diselenide. After 45 days of treatment, the rabbits were killed and the blood, liver, and brain were used for laboratory analysis. The results showed that the serum levels of total cholesterol were markedly increased in cholesterol-fed rabbits and the consumption of diphenyl diselenide decreased these levels approximately twofold in Chol/diphenyl diselenide rabbits (P < 0.05). The intake of diphenyl diselenide by hypercholesterolaemic rabbits diminished the serum and hepatic thiobarbituric acid reactive substances levels as well as the production of reactive oxygen species in the blood and brain (P < 0.05) when compared to the cholesterol group. In addition, diphenyl diselenide supplementation increased hepatic and cerebral delta-aminolevulinic dehydratase activity and hepatic non-protein thiol groups levels despite hypercholesterolaemia (P < 0.05). In summary, the results showed that diphenyl diselenide reduced the hypercholesterolaemia and the oxidative stress in cholesterol-fed rabbits.

The role of dysfunctional HDL in atherosclerosis

This review focuses on HDL function in modulating LDL oxidation and LDL-induced inflammation. Dysfunctional HDL has been identified in animal models and humans with chronic inflammatory diseases including atherosclerosis. The loss of antiinflammatory function correlated with a loss of function in reverse cholesterol transport. In animal models and perhaps in humans, dysfunctional HDL can be improved by apoA-I mimetic peptides that bind oxidized lipids with high affinity.