Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits

BACKGROUND: The beneficial effect of long-term hormone replacement therapy in terms of a decreased risk of cardiovascular disease is now generally accepted. Raloxifene, a selective estrogen receptor modulator, has demonstrated hypolipidemic properties while leaving the endometrium unstimulated. METHODS AND RESULTS: For our study of the effects of raloxifene on atherosclerosis, 75 rabbits were ovariectomized and treated with either raloxifene, 17beta-estradiol, or placebo; 25 rabbits were sham operated and treated with placebo. After 45 weeks, the raloxifene group had two thirds of the aortic atherosclerosis, as evaluated by the cholesterol content of the proximal inner part of the aorta, found in the placebo group (placebo, 577+/-55.1 nmol/mg protein; raloxifene, 397+/-53.6 nmol/mg protein; P<.05); the estrogen group had one third of the aortic atherosclerosis in the placebo group (estrogen, 177+/-32.1 nmol/mg protein; P<.001). The sham-operated group (473+/-59.6 nmol/mg protein) was not significantly different from placebo. These effects were only partly explained by the changes in serum lipids and lipoproteins, and treatment with both estrogen and raloxifene independently predicted the response in aorta cholesterol. Because plasma levels of total raloxifene were low relative to clinical values in postmenopausal women, dose-response data for raloxifene are required. CONCLUSIONS: Our findings indicate that raloxifene hydrochloride has a potentially important antiatherogenic effect, analogous to that observed with estrogen in this model.     

Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits

Bone morphogenetic proteins (BMPs) are derived from inactive precursor proteins by endoproteolytic cleavage. Here we show that processing of Nodal and Myc-tagged BMP4 is significantly enhanced by SPC1/Furin or SPC4/PACE4, providing direct evidence that regulation of BMP signaling is likely to be controlled by subtilisin-like proprotein convertase (SPC) activities. Nodal processing is dramatically enhanced if two residues adjacent to the precursor cleavage site are substituted with amino acids found at the equivalent positions of Activin, demonstrating that structural constraints at the precursor cleavage site limit the processing efficiency. However, in transfection assays, mature Nodal is undetectable either in culture supernatants or in cell lysates, despite efficient cleavage of the precursor protein, suggesting that mature Nodal is highly unstable. Domain swap experiments support this conclusion since mature BMP4 or Dorsalin are also destabilized when expressed in conjunction with the Nodal pro domain. By contrast, mature Nodal is stabilized by the Dorsalin pro domain, which mediates the formation of stable complexes. Collectively, these data show that the half-life of mature BMPs is greatly influenced by the identity of their pro regions.     

Effects of unilateral parietal lesions on spatial localization in the rat.

In the 1st of 2 experiments, rats with left or right parietal lesions and controls were tested in place and landmark navigation in the water maze. Right parietal lesions resulted in deficits in both tasks, but especially landmark navigation. Lateralized effects appeared mainly in latency to find the platform. Exp 2 investigated the role of the corpus callosum. Split-brain rats with unilateral parietal lesions were tested on the same 2 tasks. Place and landmark deficits were particularly severe, but lateralization was weaker. Callosum section had its own effect, impairing the learning of both tasks. There appear to be additive effects of unilateral cortical lesions and bisection of the hemispheres. The impairment from left lesions equaled the right-lesion deficit because of the interruption of compensatory information from the intact right hemisphere and the effect of callosum section itself. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Norethindrone acetate enhances the antiatherogenic effect of 17beta-estradiol: a secondary prevention study of aortic atherosclerosis in ovariectomized cholesterol-fed rabbits

OBJECTIVE: Premature delivery is difficult to predict and causes considerable neonatal morbidity and mortality. Despite much research, little progress has been made in timely identification of the mothers at risk. We examined the uterine cervix with ultrasonography to discover whether such a procedure would be helpful in determining which women will deliver prematurely. METHODS: We performed transvaginal ultrasound examinations in addition to routine transabdominal ultrasonography at 18 to 22 weeks' gestation in 3694 consecutive pregnant women with live singleton fetuses. We measured the length of the uterine cervix and evaluated the dilatation, if any, of the internal os. The results of cervical ultrasonography were not available to the clinicians. RESULTS: Spontaneous delivery occurred before 37 completed weeks in 88 women (2.4%) and before 35 weeks in 31 (0.8%). The relative risk of delivery before 35 weeks was 8 (95% confidence interval 3, 19) when the cervical length was 29 mm or shorter. When dilatation of the internal cervical os of 5 mm or greater was present, the relative risk of delivery before 35 weeks was 28 (95% confidence interval 12, 67). Either short cervix (29 mm or less) or dilatation of internal cervical os (5 mm or greater) was present in 3.6% of the population; this combination had a sensitivity of 29% in predicting delivery at earlier than 35 weeks. After adjusting for cervical dilatation and length by using multiple logistic regression, nulliparity also remained a risk factor for delivery before 35 weeks (odds ratio 3.6, 95% confidence interval 1.7, 7.5). CONCLUSION: Transvaginal ultrasonography performed as an addition to routine transabdominal ultrasonography at 18 to 22 weeks helps to identify many patients at significant risk for prematurity; however, low sensitivity and low positive predictive value limit its usefulness in screening low-risk obstetric populations.     

Quantitative analyses of lesion areas of coronary atherosclerosis in cholesterol-fed rabbits

A simple method to quantitatively evaluate atherosclerosis in the rabbit coronary arteries by measuring macroscopic lesion areas (%) was attempted in the present study. Sixteen rabbits were fed a 0.5% cholesterol diet for 15 weeks and then 9 rabbits were sacrificed whereas the remaining 7 rabbits were maintained for further 9 weeks on a normal chow (at week 24). The left circumflex coronary arteries (LCX) were excised from the rabbit hearts under stereoscopic observation. The prepared arterial strips of LCX were 38.7 +/- 7.1 mm long and all of them reached the cardiac apex from the orifice. At week 15, the lesion area in LCX was negligible (3.2 +/- 0.4%) whereas the aortic lesions significantly developed (50.0 +/- 7.6%). At week 24, atherosclerotic lesions in both LCX and aortas increased to 32.8 +/- 9.2% and 85.9 +/- 5.6%, respectively. This is the first report that determined the luminal surface areas of atherosclerotic lesions in rabbit coronary arteries. This method may be more practical and useful for quantitative evaluation of coronary atherosclerosis in a large number of rabbits than histological observations of serial sections of rabbit hearts.     

Increased bile acid pool inhibits cholesterol 7 alpha-hydroxylase in cholesterol-fed rabbits

BACKGROUND & AIMS: Cholesterol feeding unexpectedly inhibits cholesterol 7 alpha-hydroxylase in rabbits. The aim of this study was to explore the mechanism. METHODS: Twenty male New Zealand white rabbits were fed regular chow with and without 2% cholesterol for 10 days followed by 7 days of bile drainage. The activities of hepatic cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase that control bile acid synthesis in classic and alternative pathways were related to the size and composition of bile acid pool. RESULTS: After feeding cholesterol, plasma and hepatic cholesterol concentrations increased, the bile acid pool doubled (from 254 +/- 44 to 533 +/- 51 mg; P < 0.001), cholesterol 7 alpha-hydroxylase activity decreased 68% (P < 0.01), but sterol 27-hydroxylase activity increased 66% (P < 0.05) with increased cholic acid synthesis (P < 0.01). Bile drainage in the cholesterol-fed rabbits depleted the bile acid pool and stimulated down-regulated cholesterol 7 alpha-hydroxylase activity 11.4-fold (P < 0.001), although hepatic cholesterol remained elevated. Hepatic sterol 27-hydroxylase activity was unaffected. CONCLUSIONS: Feeding cholesterol increased hepatic cholesterol and stimulated sterol 27-hydroxylase and alternative bile acid synthesis, which expanded the bile acid pool and inhibited cholesterol 7 alpha-hydroxylase in rabbits. In distinction, hepatic sterol 27-hydroxylase was insensitive to changes in the bile acid pool.     

Simvastatin inhibits myointimal hyperplasia following carotid artery injury in cholesterol-fed rabbits

The effect of simvastatin, a potent inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) was evaluated in an experimental model of myointimal hyperplasia in cholesterol-fed rabbits. Myointimal hyperplasia was induced by an air-drying injury of the left carotid artery followed by a 2%-cholesterol diet for 14 days. A 2-week oral treatment with simvastatin (6 mg/kg/day, p.o.) significantly lowered the circulating levels of cholesterol and triglycerides (41% and 49% inhibition respectively) as well as the low density lipoprotein (LDL)-cholesterol and high density lipoprotein (HDL)-cholesterol levels. Simvastatin also strongly affected the uptake of cholesterol in the arteries occurring as a consequence of vascular injury (44% inhibition, P < 0.001). Morphometric analysis revealed that both the intima and the media areas increased substantially 2 weeks after the lesion and showed a considerable smooth muscle cell accumulation in the neointima together with the presence of numerous foam cells. A 16-day oral treatment with simvastatin strongly reduced smooth muscle cells hyperplasia occurring in both the media and the intima following deendothelialization (19% and 60% inhibition respectively) suggesting that simvastatin may be a useful inhibitor of restenosis which occurs following vascular injury.     

Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin

BACKGROUND: We investigated whether L-arginine induces regression of preexisting atheromatous lesions and reversal of endothelial dysfunction in hypercholesterolemic rabbits, whether similar effects can be obtained by cholesterol-lowering therapy with lovastatin, and which mechanism leads to these effects. METHODS AND RESULTS: Rabbits were fed 1% cholesterol for 4 weeks and 0.5% cholesterol for an additional 12 weeks. Two groups of cholesterol-fed rabbits were treated with L-arginine (2.0% in drinking water) or lovastatin (10 mg/d) during weeks 5 through 16. Systemic nitric oxide (NO) formation was assessed as the urinary excretion rates of nitrate and cGMP in weekly intervals. Cholesterol feeding progressively reduced urinary nitrate excretion to approximately 40% of baseline (P<.05) and increased plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthesis inhibitor. Dietary L-arginine reversed the reduction in plasma L-arginine/ADMA ratio and partly restored urinary excretion of nitrate and cGMP (each P<.05 vs cholesterol) but did not change plasma cholesterol levels. L-Arginine completely blocked the progression of carotid intimal plaques, reduced aortic intimal thickening, and preserved endothelium-dependent vasodilator function. Lovastatin treatment reduced plasma cholesterol by 32% but did not improve urinary nitrate or cGMP excretion or endothelium-dependent vasodilation. Lovastatin had a weaker inhibitory effect on carotid plaque formation and aortic intimal thickening than L-arginine. L-Arginine inhibited but lovastatin potentiated superoxide radical generation in the atherosclerotic vascular wall. CONCLUSIONS: Dietary L-arginine improves NO-dependent vasodilator function in cholesterol-fed rabbits and completely blocks the progression of plaques via restoration of NO synthase substrate availability and reduction of vascular oxidative stress. Lovastatin treatment has a weaker inhibitory effect on the progression of atherosclerosis and no effect on vascular NO elaboration, which may be due to its stimulatory effect on vascular superoxide radical generation.     

HL-004, the ACAT inhibitor, prevents the progression of atherosclerosis in cholesterol-fed rabbits

HL-004, N-(2,6-diisopropylphenyl) tetradecylthioacetamide, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated concerning the possible prevention of hyperlipidemia and atherosclerosis in 1% cholesterol-fed rabbits. HL-004 (0.2, 5 and 25 mg/kg) was orally administered once a day for 12 weeks. HL-004 inhibited the rise of total serum cholesterol at a dose of 5 mg/kg and over. In the thoracic aorta, HL-004 at the doses of 5 mg/kg and 25 mg/kg reduced the total cholesterol content by 56.3% and 84.2% compared with control, and decreased ACAT activity, dose-dependently. HL-004 also attenuated the development of aortic lesions. The area of atherosclerotic lesions was reduced by 30.3% with 5 mg/kg of HL-004 and 100% with 25 mg/kg. In this study, we suggest that the main reason for HL-004 preventing the progression of atherosclerosis is its hypocholesterolemic effect due to the inhibition of cholesterol absorption in the intestine.     

Possible mechanism for the anti-atherosclerotic action of the calcium channel blocker AE0047 in cholesterol-fed rabbits

The genetics of resistance to disease is an area of great interest in agriculturally important plant and animal species. Selective breeding for resistance to pathogens in plants, animals and insects has demonstrated that resistance and susceptibility to pathogens are controlled by both genetic and environmental factors. The immune loci causally involved in susceptibility and resistance to disease are currently unknown. However, novel enabling molecular technologies promise to assist in unravelling the genetics of the host response to infectious diseases in new ways, and ultimately to improve seed stock genetics.     

Cholesterol mobilization and regression of atheroma in cholesterol-fed rabbits induced by large unilamellar vesicles

The antiatherogenic properties of repeated injections of egg phosphatidylcholine large unilamellar vesicles (LUVs) of 100 nm diameter were tested in an experimental model for atherosclerosis. Forty eight rabbits were divided into two diet groups fed standard rabbit chow or fed a cholesterol-enriched diet (0.5% by weight) to induce the formation of atherosclerotic lesions. Prior to the initiation of LUV therapy, the cholesterol diet was ceased and all animals were returned to standard rabbit chow. The treatment protocol consisted of a total of 10 bolus injections of vesicles, at a phospholipid dose of 300 mg/kg body weight or the equivalent volume of saline, with one injection given to each animal every 10 days. LUV injections brought about a large movement of cholesterol into the blood pool and resulted in a significant reduction in the cholesterol content as well as the degree of surface plaque involvement of aortic tissue in atherosclerotic animals. Most notably, the thoracic aorta of LUV-treated animals exhibited a 48% reduction in tissue cholesterol content per gram of protein compared to saline-treated controls. Histochemical analyses revealed that aortas from animals receiving the repeated injections of LUVs displayed less cholesterol deposits in lesions, and a moderate reduction in intimal-to-medial thickness. This regression of atheroma, induced by LUV therapy, was observed even though animals possessed persistent elevated plasma cholesterol levels after the cholesterol-enriched diet was ceased. These results suggest that repeated injections of LUVs, working with endogenous HDL, may be a useful therapy in the management of atherosclerosis.     

Regression of injury-induced atheromatous lesions in rabbits

Toxoplasma gondii undergoing endo-enteric development in the small intestine of the cat affects the ultrastructure of the epithelial cells. The epithelial cells from infected cats have swollen rough endoplasmic reticulum and the mitochondria may be swollen with degenerate cristae. A statistically significant shortening of the microvilli of the epithelial cells was demonstrated. It appeared that the effect on the microvilli length was related to the parasite distribution within the small intestine. These changes occur in both cells with and without parasites present at the level of the sections studied. The abnormalities are quickly rectified after the disappearance of the endo-enteric forms of Toxoplasma.     

Intellectual stability in children with unilateral brain lesions

Developmental differences in behavior and self-perception were examined in a group of 44 preschool and school-age children referred for evaluation of sexual abuse and 41 comparison children with no history of sexual abuse, matched on age and gender, and from a similar socioeconomic background. Children suspected of having been sexually abused were rated by their parents as having more internalizing and externalizing problems than comparison children. When children rated their self-competence and social acceptance, there were no group differences between children based on their abuse status; however, there was significant within-group variation among the children suspected of having been sexually abused. Preschool children had elevated scores of perceived competence and social acceptance, and school-age children had depressed scores. There were no age differences among the children in the comparison group. The results suggest that among children suspected of abuse, not only does their self-perception vary by their developmental level, but preschool children may respond with elevated perceptions of themselves. Focusing on individual differences in children's response to suspicions of sexual abuse enables us to identify risk and protective factors that contribute to the psychological outcomes of child sexual abuse.     

Effect of pravastatin, a HMG CoA reductase inhibitor, on blood lipids and aortic lipidosis in cholesterol-fed White Carneau pigeons

The goals of this study were (a) to examine differing views on the relationship between self-report of emotion and physiological expression of emotion, (b) to differentiate between negative emotional contexts during imagery using facial electromyogram (EMG), and (c) to describe the facial muscle patterning and autonomic physiology of situations that involve expelling or avoiding disgusting sensory stimulation. Fifty subjects imagined situations eliciting disgust, anger, pleasure, and joy in 8-s trials using a tone-cued imagery procedure. Heart rate, skin conductance level, and facial EMG at the corrugator, zygomatic, and levator labii superioris/alesque muscle regions were recorded during imagery, and self-reports of emotion were collected after imagery trials. Self-reports of emotion produced results consistent with the affective categorization of the images. Activity at the levator labii region was higher during disgust than during anger imagery. Corrugator region increase characterized the negative as compared with the positive emotional contents, and activity at the zygomatic region was higher during joy imagery than during the other three emotions. Heart rate acceleration was greater during disgust, anger, and joy imagery than during pleasant imagery. Disgust imagery could be discriminated from anger imagery using facial EMG, and the expressive physiology of disgust was occasioned by the action set of active avoidance or rejection of sensory stimulation.     

Ipsiversive progression and unilateral posterior cortical lesions in the rat.

Hypothesized that nonvisual deficits ascribed to visual cortex lesions reflect an impairment in spatial progression. To evaluate this possibility, 64 male hooded rats were enucleated, subjected to unilateral neocortical lesions, and tested for ipsiversive progression. The hypothesis was not supported since destruction of the visual cortex alone did not produce the effect while similar-sized, more anteriorly placed, lesions did. Moreover, there was nothing to indicate that visual cortex destruction in combination with an effective lesion enhanced the effect. Results support those who have criticized the belief that the visual cortex carries out nonvisual functions. (17 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Factor-defined abilities in patients with unilateral brain lesions.

Administered a battery of 4 tests adapted from the structure of intellect model of differential abilities to 72 adults with right and left cerebral lesions and normals. Findings show that both brain-damaged groups exhibited slower response times than normals and that there was a relation between locus of the lesion and performance. However, results do not sufficiently demonstrate the advantage of factor-defined ability tests over tests of global intelligence and question the validity of these factor-defined tests in that they do not distinguish behaviors that are factorially distinct in normal populations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)