Alter Serum Cholesterol Research Articles

Maternal history of Alzheimer's disease predisposes to altered serum cholesterol levels in adult offspring.

Controversial findings regarding the association between serum cholesterol levels and Alzheimer's disease (AD) have been identified through observational studies. The genetic basis shared by both factors and the causality between them remain largely unknown. The objective of this study is to examine the causal impact of maternal history of AD on changes in serum cholesterol levels in adult offspring. By retrieving genetic variants from summary statistics of large-scale genome-wide association study of maternal history of AD (European-based: Ncase = 27 696, Ncontrol = 260 980). The causal association between genetically predicted maternal history of AD and changes in serum cholesterol levels in adult offspring was examined using the two-sample Mendelian randomization (MR) method. Causal impact estimates were calculated using single-nucleotide polymorphisms in both univariable MR (UMR) and multivariable MR (MVMR) analyses. Additionally, other approaches, such as Cochran's Q test and leave-one-out variant analysis, were employed to correct for potential biases. The results of UMR presented that genetically predicted maternal history of AD was positively associated with hypercholesterolemia (OR = 1.014; 95% CI: 1.009-1.018; p < 0.001), total cholesterol (OR = 1.29; 95% CI: 1.134-1.466; p < 0.001) and low-density lipoprotein (OR = 1.525; 95% CI: 1.272-1.828; p < 0.001) among adult offspring. Genetic predisposition for maternal history of AD to be negatively associated with high-density lipoprotein (OR = 0.889; 95% CI: 0.861-0.917; p < 0.001). The MVMR analysis remained robust and significant after adjusting for diabetes and obesity in offspring. Sufficient evidence was provided in this study to support the putative causal impact of maternal history of AD on the change of serum cholesterol profile in adult offspring. In clinical practice, priority should be given to the detection and monitoring of cholesterol levels in individuals with a maternal history of AD, particularly in the early stages.

Detection of Porcine Deltacoronavirus RNA in the Upper and Lower Respiratory Tract and Biliary Fluid and the Effect of Infection on Serum Cholesterol Levels and Blood T Cell Population Frequencies in Gnotobiotic Piglets

Porcine deltacoronavirus (PDCoV) was first identified approximately a decade ago, but much is still obscure in terms of its pathogenesis. We aimed to further characterize PDCoV infection by investigating the presence of virus in respiratory and biliary tissues or fluids; T cell population frequencies in blood; and altered serum cholesterol levels. Twelve, 6-day-old, gnotobiotic piglets were inoculated oronasally with PDCoV OH-FD22 (2.6 × 107 FFU/pig). Six control piglets were not inoculated. Rectal swab (RS), nasal swab (NS), nasal wash (NW), bronchoalveolar lavage (BAL), and biliary fluid (BF) samples were collected at 2, 4, and 7 days post-inoculation (DPI) and tested for PDCoV RNA by RT-qPCR. Blood T cell populations and serum cholesterol levels were determined by flow cytometry and a colorimetric assay, respectively. Moderate to high, and low to moderate titers of PDCoV RNA were detected in RS and in NS, NW, BAL, and BF samples, respectively, of inoculated piglets. There were trends toward decreased CD4+CD8-, CD4-CD8+, and CD4+CD8+ blood T cell frequencies in inoculated piglets. Furthermore, serum cholesterol levels were increased in inoculated piglets. Overall, we found that PDCoV infection does not exclusively involve the intestine, since the respiratory and biliary systems and cholesterol metabolism also can be affected.

Combined Anthocleista vogelii and Alstonia boonei Stem Barks Extract Alleviates Hyperlipidaemia and Renal Malfunctions in Benign Prostatic Hyperplasia-Induced Rats

Benign prostatic hyperplasia (BPH) is a urological disease prevalent among the ageing male population, which impairs the quality of life, including hyperlipidaemia and a decline in renal functions. Combining Anthocleista vogelii and Alstonia boonei stem bark extract has effectively managed BPH and its associated complications. This study evaluated the effects of a combined Anthocleista vogelii and Alstonia boonei stem bark extract (CAASBE) on the lipid profile and renal functions of rats induced benign prostatic hyperplasia with testosterone propionate injection. The study comprised five treatment groups, with groups 1 – 5 being the normal control, BPH control, standard control, BPH+200 mg/kg CAASBE, and BPH+400 mg/kg CAASBE, respectively. BPH was induced in the groups 2 – 4 rats by subcutaneous administration of testosterone propionate injection (5 mg/kg) for 28 days, and treatment with Finasteride and CAASBE were administered orally. The BPH control rats exhibited a significant (p &lt; 0.05) increase in the total serum cholesterol, triacylglycerol (TAG), low-density lipoprotein cholesterol (LDL-C), urea, creatinine and significant (p &lt; 0.05) decline in the serum high-density lipoprotein cholesterol (HDL-C) compared to the normal control. Conversely, treatment of the BPH rats with 200 and 400 mg/kg of CAASBE significantly (p &lt; 0.05) reversed the altered total serum cholesterol, TAG, LDL-C, HDL-C, urea and creatinine to normal levels comparable to that of the normal control and standard control respectively. These findings show that CAASBE alleviates hyperlipidaemia and renal malfunctions in the BPH rats suggesting it could be effective in managing BPH complication.

Effects of dibutyl phthalate and di (2-ethylhexyl) phthalate on hepatic structure and function of adult male mice.

The objective of the present research was to determine if dibutyl phthalate (DBP) and di-(2-ethylhexyl) phthalate (DEHP) alone and combined exposure induced pathological alterations in laboratory reared albino mice. Adult male mice were equally divided (n = 10) into Control, corn oil (CO), DBP, DEHP, and DBP+DEHP treated groups. Dibutyl phthalate (250 mg/kg), DEHP (300 mg/kg), and DBP+DEHP (250+300 mg/kg), respectively, were administered by oral gavage mixed in corn oil (0.2mL) for 28days. All animals were sacrificed following 28days of treatment and blood was collected for serum lipid profiles and liver function tests. Liver samples were also collected for observation of histological changes. Microphotographs of hematoxylin and eosin-stained sections were used for computer-based micrometry. CO, DBP, DEHP, and DBP+DEHP treatment resulted in a significant increase in the mean body and liver weights as compared with the Control group. Histological examination of the livers with DBP and/or DEHP treatment showed marked alterations leading to hepatic hypertrophy. In the treated groups, a significant increase in the mean number of mononucleated, binucleated cells, and oval cells per unit area was noticed with disorganized trabecular arrangement as compared with the Control group. Treatment with DBP and/or DEHP resulted in large regeneration zones in the liver and an increased relative nucleo-cytoplasmic index of mononuclear shepatocytes when compared with the Control group. All treatments caused a significant increases in the liver enzymes and proteins as well as altered serum cholesterol, triglycerides, LDL, and VLDL levels. The histopathological and serological findings confirmed the toxic potentials to hepatic tissue of DBP and DEHP either given alone or in combination.

Derivation of a Human In Vivo Benchmark Dose for Perfluorooctanoic Acid From ToxCast In Vitro Concentration-Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation.

A computational workflow which integrates physiologically based kinetic (PBK) modeling, global sensitivity analysis (GSA), approximate Bayesian computation (ABC), and Markov Chain Monte Carlo (MCMC) simulation was developed to facilitate quantitative in vitro to in vivo extrapolation (QIVIVE). The workflow accounts for parameter and model uncertainty within a computationally efficient framework. The workflow was tested using a human PBK model for perfluorooctanoic acid (PFOA) and high throughput screening (HTS) in vitro concentration–response data, determined in a human liver cell line, from the ToxCast/Tox21 database. In vivo benchmark doses (BMDs) for PFOA intake (ng/kg BW/day) and drinking water exposure concentrations (µg/L) were calculated from the in vivo dose responses and compared to intake values derived by the European Food Safety Authority (EFSA). The intake benchmark dose lower confidence limit (BMDL5) of 0.82 was similar to 0.86 ng/kg BW/day for altered serum cholesterol levels derived by EFSA, whereas the intake BMDL5 of 6.88 was six-fold higher than the value of 1.14 ng/kg BW/day for altered antibody titer also derived by the EFSA. Application of a chemical-specific adjustment factor (CSAF) of 1.4, allowing for inter-individual variability in kinetics, based on biological half-life, gave an intake BMDL5 of 0.59 for serum cholesterol and 4.91 (ng/kg BW/day), for decreased antibody titer, which were 0.69 and 4.31 the EFSA-derived values, respectively. The corresponding BMDL5 for drinking water concentrations, for estrogen receptor binding activation associated with breast cancer, pregnane X receptor binding associated with altered serum cholesterol levels, thyroid hormone receptor α binding leading to thyroid disease, and decreased antibody titer (pro-inflammation from cytokines) were 0.883, 0.139, 0.086, and 0.295 ng/ml, respectively, with application of no uncertainty factors. These concentrations are 5.7-, 36-, 58.5-, and 16.9-fold lower than the median measured drinking water level for the general US population which is approximately, 5 ng/ml.

Sheep and cattle exposed to Mycobacterium avium subspecies paratuberculosis exhibit altered total serum cholesterol profiles during the early stages of infection

Pathogenic mycobacteria such as Mycobacterium tuberculosis are capable of utilising cholesterol as a primary carbon-based energy source in vitro but there has been little research examining the significance of cholesterol in vivo. Johne’s disease is a chronic enteric disease of ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP). This study sought to evaluate the levels of total serum cholesterol in the host following exposure to MAP. Blood samples were collected from both sheep and cattle prior to experimental challenge with MAP and at monthly intervals post-challenge. Total serum cholesterol levels in sheep challenged with MAP were significantly elevated at 9 weeks post-inoculation (wpi) in comparison to controls. When stratified based on disease outcome, there was no significant difference in serum cholesterol at the timepoints examined between MAP exposed sheep that were susceptible and those that were resistant to Johne’s disease. There was a similar elevation in serum cholesterol at 9 wpi in cattle with histopathological gut lesions associated with disease or those with an early high IFN-γ response. Total serum cholesterol in exposed cattle was significantly lower when compared to controls at 13 wpi. Taken together, these results demonstrate changes in serum cholesterol following MAP exposure and disease progression which could reflect novel aspects of the pathogenesis and immune response associated with MAP infection in both sheep and cattle.

The Effects of Dietary Flavonoid Supplementation on the Antioxidant Status of Laying Hens

ABSTRACT Ninety-six 28-week-old Lohmann White laying hens were utilized to test the antioxidant effects of flavonoids (hesperidin, naringin, and quercetin at 0.5 g/kg diet) during an 8-wk experimental period. At the end of the experiment blood samples were collected to determine total protein, cholesterol, and malondialdehyde (MDA) serum levels as well as activities of glutathione reductase (GR), glutathione peroxidase (GSH-Px), glutathione- S -transferase (GST), and superoxide dismutase (SOD) and level of glutathione (GSH) in erythrocyte lysates. Data were analyzed using one-way ANOVA. Naringin supplementation did not alter serum cholesterol concentration, whereas hesperidin and quercetin supplementations decreased serum cholesterol concentration. Naringin and quercetin supplementations did not affect serum protein concentration. All flavonoids decreased MDA concentration as well as increased GSH-Px, GR, GST, and SOD activities and GSH level, being quercetion superior to hesperidin and naringin. In conclusion, flavonoids, especially quercetin, exert antioxidant activity, which may help improve wellbeing when laying hens are exposed to stressors.

P.1.e.023 Functional mutations in CADPS identified in patients with early-onset bipolar disorder

Men and postmenopausal women exhibit a higher risk for atherosclerosis than premenopausal women. These differences were often attributed to sex steroids, but the role of estrogen and testosterone in atherosclerosis are more complex than anticipated. Cross-sex hormone therapy of transsexuals is an interesting model, which has been used to study hormonal effects on serum lipid profile, insulin resistance, and body composition. However, studies on macrophage cholesterol efflux, the first step in reverse cholesterol transport, are not available.The aim of this study was to evaluate the effect of cross-sex hormone therapy in transsexuals on the capacity of serum to accept cholesterol from macrophages.Cholesterol acceptor capacity (CAC) of serum from transsexuals before and after at least 6 months of hormone treatment was measured using macrophage tissue culture models.CAC of serum using the human acute monocytic leukemia cell line (THP-1 cells).Unexpectedly, the CAC of serum from male to female (MtF) transsexuals was not increased, but decreased after hormone therapy. Serum from female to male (FtM) transsexuals showed no changes in CAC.Despite drastic changes in hormone status, no increase in CAC was detected in MtF patients, and no alteration in CAC was seen in FtM patients. These data further challenge the traditional view that estrogen and testosterone exert beneficial and detrimental effects, respectively, on lipoprotein metabolism and ultimately atherosclerosis. Wultsch A, Kaufmann U, Ott J, Stojakovic T, Scharnagl H, Stangl H, and Strobl WM. Profound changes in sex hormone levels during cross-sex hormone therapy of transsexuals do not alter serum cholesterol acceptor capacity. J Sex Med 2015;12:1436–1439.

Profound Changes in Sex Hormone Levels during Cross-Sex Hormone Therapy of Transsexuals do not Alter Serum Cholesterol Acceptor Capacity

Men and postmenopausal women exhibit a higher risk for atherosclerosis than premenopausal women. These differences were often attributed to sex steroids, but the role of estrogen and testosterone in atherosclerosis are more complex than anticipated. Cross-sex hormone therapy of transsexuals is an interesting model, which has been used to study hormonal effects on serum lipid profile, insulin resistance, and body composition. However, studies on macrophage cholesterol efflux, the first step in reverse cholesterol transport, are not available. The aim of this study was to evaluate the effect of cross-sex hormone therapy in transsexuals on the capacity of serum to accept cholesterol from macrophages. Cholesterol acceptor capacity (CAC) of serum from transsexuals before and after at least 6 months of hormone treatment was measured using macrophage tissue culture models. CAC of serum using the human acute monocytic leukemia cell line (THP-1 cells). Unexpectedly, the CAC of serum from male to female (MtF) transsexuals was not increased, but decreased after hormone therapy. Serum from female to male (FtM) transsexuals showed no changes in CAC. Despite drastic changes in hormone status, no increase in CAC was detected in MtF patients, and no alteration in CAC was seen in FtM patients. These data further challenge the traditional view that estrogen and testosterone exert beneficial and detrimental effects, respectively, on lipoprotein metabolism and ultimately atherosclerosis.

Abstract 461: Cilnidipine Attenuated Angiotensin II-induced Abdominal Aortic Aneurysms in Apolipoprotein E-deficient Mice

Objective: Chronic infusion of angiotensin II (AngII) promotes development of abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Previous studies have shown that local inflammation and increased oxidative stress plays an important role on formation of AAAs. In addition, it is reported that voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by AngII in mice. Therefore, we hypothesized that cilnidipine, an N/L-type calcium channel blocker, exerts vasoprotective effect by inhibiting inflammation and superoxide generation in mice. The purpose of this study was to evaluate whether cilnidipine influenced AngII-induced AAAs. Methods and Results: Male apolipoprotein E deficient mice (8-12 weeks old) were fed a normal laboratory diet. Mice were infused subcutaneously with either cilnidipine or vehicle by osmotic minipumps. Three days later, mice were also infused subcutaneously with either AngII (1,000 ng/kg/min, n = 14-16) or saline (n = 4) each by osmotic minipumps for 4 weeks. AngII increased systolic blood pressure. Cilnidipine decreased blood pressure in AngII-infused mice, but had not effect during saline infusion. AngII infusion did not alter serum cholesterol concentrations. However, cilnidipine slightly decreased serumcholesterol concentrations in AngII-infused mice. Cilnidipine had no effect on body weights, heart rates, and urine total protein, but mildly restored plasma renin activity that were suppressed by AngII infusion. Cilnidipine did not affect ex vivo measurement of maximal diameter of abdominal aorta (1.04 ± 0.09 mm vs 1.11 ± 0.06 mm, n.s.) in saline infused mice. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas, but was attenuated by cilnidipine (1.79 ± 0.59 mm vs 1.26 ± 0.38 mm, P &lt; 0.05). In addition, cilnidipine significantly reduced the incidence of AngII-induced AAAs (Cilnidipine: 38 %, Vehicle: 88 %; P &lt; 0.05). Furthermore, gelatin zymography demonstrated that cilnidipine diminished AngII-induced increase in aortic MMP-9 protein abundance. Conclusion: Cilnidipine attenuated AngII-induced AAAs in male apolipoprotein E deficient mice.

Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9.

Patients with mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene have hypercholesterolemia and are at high risk of adverse cardiovascular events. We aimed to stably express the pathological human D374Y gain-of-function mutant form of PCSK9 (PCSK9(DY)) in adult wild-type mice to generate a hyperlipidemic and proatherogenic animal model, achieved with a single systemic injection with adeno-associated virus (AAV). We constructed an AAV-based vector to support targeted transfer of the PCSK9(DY) gene to liver. After injection with 3.5×10(10) viral particles, mice in the C57BL/6J, 129/SvPasCrlf, or FVB/NCrl backgrounds developed long-term hyperlipidemia with a strong increase in serum low-density lipoprotein. Macroscopic and histological analysis showed atherosclerotic lesions in the aortas of AAV-PCSK9(DY) mice fed a high-fat-diet. Advanced lesions in these high-fat-diet-fed mice also showed evidence of macrophage infiltration and fibrous cap formation. Hepatic AAV-PCSK9(DY) infection did not result in liver damage or signs of immunologic response. We further tested the use of AAV-PCSK9(DY) to study potential genetic interaction with the ApoE gene. Histological analysis of ApoE(-/-) AAV-PCSK9(DY) mice showed a synergistic response to ApoE deficiency, with aortic lesions twice as extensive in ApoE(-/-) AAV-PCSK9(DY)-transexpressing mice as in ApoE(-/-) AAV-Luc controls without altering serum cholesterol levels. Single intravenous AAV-PCSK9(DY) injection is a fast, easy, and cost-effective approach, resulting in rapid and long-term sustained hyperlipidemia and atherosclerosis. We demonstrate as a proof of concept the synergy between PCSK9(DY) gain-of-function and ApoE deficiency. This methodology could allow testing of the genetic interaction of several mutations without the need for complex and time-consuming backcrosses.

Polymorphism in Integrin ITGA2 is Associated with Ischemic Stroke and Altered Serum Cholesterol in Chinese Individuals

Recent studies have reported contrasting results regarding the association of polymorphisms in two integrin genes, ITGA2 and ITGB3, with ischemic stroke. The present study aimed to investigate the correlation between the ITGA2 C807T and ITGB3 T176C polymorphic loci with ischemic stroke, as well as plasma lipid and lipoprotein levels. Case control study. Human venous blood samples were collected from patients admitted for ischemic stroke (n=350, 'patients') and healthy individuals (n=300, 'controls'). Blood was genotyped at these loci by polymerase chain reaction-restriction fragment length polymorphism. Plasma lipid and lipoprotein levels were measured by routine enzymatic, masking, and turbidimetry methods. As expected, total cholesterol, triglycerides, and low-density lipoprotein were all significantly higher in patients than in controls (p<0.05). Genotype and allele frequencies of ITGA2 C807T were significantly different between patients and controls (p<0.05), but no difference was detected in genotype or allele frequencies for ITGA3 T176C. For ITGA-2, the T allele conferred a 1.226 times higher relative risk of ischemic stroke than the C allele (odds ratio=1.226, 95% confidence interval=1.053-1.428). Similarly, total cholesterol was higher in T allele carriers than in non-carriers (p<0.05). ITGA2 C807T polymorphism is associated with ischemic stroke, with the T allele acting as a susceptibility allele that appears to confer increased cholesterol levels.

Ginseng Berry Extract Prevents Atherogenesis via Anti-Inflammatory Action by Upregulating Phase II Gene Expression

Ginseng berry possesses higher ginsenoside content than its root, which has been traditionally used in herbal medicine for many human diseases, including atherosclerosis. We here examined the antiatherogenic effects of the Korean ginseng berry extract (KGBE) and investigated its underlying mechanism of action in vitro and in vivo. Administration of KGBE decreased atherosclerotic lesions, which was inversely correlated with the expression levels of phase II genes to include heme oxygenase-1 (HO-1) and glutamine-cysteine ligase (GCL). Furthermore, KGBE administration suppressed NF-κB-mediated expression of atherogenic inflammatory genes (TNF-α, IL-1β, iNOS, COX-2, ICAM-1, and VCAM-1), without altering serum cholesterol levels, in ApoE−/− mice fed a high fat-diet. Treatment with KGBE increased phase II gene expression and suppressed lipopolysaccharide-induced reactive oxygen species production, NF-κB activation, and inflammatory gene expression in primary macrophages. Importantly, these cellular events were blocked by selective inhibitors of HO-1 and GCL. In addition, these inhibitors reversed the suppressive effect of KGBE on TNF-α-mediated induction of ICAM-1 and VCAM-1, resulting in decreased interaction between endothelial cells and monocytes. These results suggest that KGBE ameliorates atherosclerosis by inhibiting NF-κB-mediated expression of atherogenic genes via upregulation of phase II enzymes and thus has therapeutic or preventive potential for atherosclerosis.

Specific loss of Toll-like receptor 2 on bone marrow derived cells decreases atherosclerosis in LDL receptor null mice*The senior author, Stewart C. Whitman, passed away on 19 February 2010. The manuscript has been communicated by Ross W. Milne (e-mail: rmilne@ottawaheart.ca) and Yves L. Marcel (e-mail: ylmarcel@ottawaheart.ca), University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.

Innate immunity and, notably, Toll-like receptors (TLR), have an important role in atherogenesis. We have tested the hypothesis that the selective loss of TLR-2 by cells of bone marrow (BM) origin will protect low-density receptor-deficient (Ldlr −/−) mice from both early- and late-stage atherosclerosis. BM cells from Tlr2+/+ and Tlr2−/− littermates were used to reconstitute lethally irradiated Ldlr−/− mice. Following a recovery period, mice were placed either on a diet containing 21% saturated fat – 0.15% cholesterol for 8 weeks to study early-stage atherosclerosis, or on a diet richer in cholesterol (1.5%) for 16 weeks to study late-stage atherosclerosis. Donor cell Tlr2 genotype did not alter serum cholesterol levels or lipoprotein profiles in recipient animals. After 8 weeks on the 0.15% cholesterol diet, deficiency of TLR-2 expression on cells of BM origin reduced atherosclerosis in the aortic root and the aortic arch in both genders of mice. In contrast, the BM recipients who received the 1.5% cholesterol diet for 16 weeks showed much larger lesions in the aortic root, and TLR-2 deficiency in BM cells failed to provide protection. Thus, TLR-2 expression in BM-derived cells contributes primarily to early stage atherosclerosis.

OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids

The organic solute and steroid transporter, Ost alpha-Ost beta, is an unusual heteromeric carrier that appears to play a central role in the transport of bile acids, conjugated steroids, and structurally-related molecules across the basolateral membrane of many epithelial cells. The transporter's substrate specificity, transport mechanism, tissue distribution, subcellular localization, transcriptional regulation, as well as the phenotype of the recently characterized Ost alpha-deficient mice all strongly support this model. In particular, the Ost alpha-deficient mice display a marked defect in intestinal bile acid and conjugated steroid absorption; a decrease in bile acid pool size and serum bile acid levels; altered intestinal, hepatic and renal disposition of known substrates of the transporter; and altered serum triglyceride, cholesterol, and glucose levels. Collectively, the data indicate that Ost alpha-Ost beta is essential for bile acid and sterol disposition, and suggest that the carrier may be involved in human conditions related to imbalances in bile acid or lipid homeostasis.

Androgen Increases AT1a Receptor Expression in Abdominal Aortas to Promote Angiotensin II–Induced AAAs in Apolipoprotein E–Deficient Mice

Castration of male apolipoprotein E-deficient (apoE-/-) mice reduces angiotensin II (Ang II)-induced abdominal aorta aneurysms (AAAs) to that of female mice. The purpose of this study was to determine whether this reduction is attributable to androgen-mediated regulation of aortic Ang II type 1A receptors (AT1aR). AT1aR mRNA abundance in the AAA-prone region of abdominal aortas was 8-fold greater compared to thoracic aortas of male but not female mice. AT1aR mRNA abundance decreased after castration in abdominal but not thoracic aortas of male mice. Dihydrotestosterone (DHT, 0.16 mg/d) administration to castrated male mice restored AT1aR mRNA abundance in abdominal aortas but had no effect in thoracic aortas. DHT also increased AT1aR mRNA abundance in abdominal aortas from female mice. Castrated male or female apoE-/- mice were administered DHT during infusion of saline or Ang II (1000 ng/kg/min for 28 days). DHT administration did not alter serum cholesterol concentrations, lipoprotein distributions, or atherosclerotic lesion areas in either male or female mice. However, administration of DHT increased AAA incidence in male (27% placebo versus 75% DHT) and female mice (28% placebo versus 64% DHT). Androgen promotes AT1aR mRNA abundance in abdominal aortas associated with increased Ang II-induced AAAs.

Comparison of the antiatherosclerotic effects of dihydropyridine calcium channel blocker and HMG-CoA reductase inhibitor on hypercholesterolemic rabbits

The antiatherosclerotic effects of the dihydropyridine-type calcium channel blocker, benidipine hydrochloride (benidipine), and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin sodium (pravastatin), were compared in hypercholesterolemic rabbits. Male, New Zealand white rabbits were fed a 0.5% cholesterol diet. Pravastatin (10 mg/kg) or benidipine (10 mg/kg) was orally administered once daily after start of feeding. After 8 weeks of cholesterol feeding, serum cholesterol was increased and endothelial function of thoracic aorta was impaired. Pravastatin prevented elevation of serum cholesterol and aortic tunica intima hyperplasia. Although benidipine had little effect on serum cholesterol, it significantly inhibited aortic tunica intima hyperplasia and impairment of endothelial function. Expression levels of the vascular cell adhesion molecule-1 (VCAM-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mRNA in aorta of hypercholesterolemic rabbit were higher than those of normal rabbit. Benidipine significantly prevented upregulation of VCAM-1 mRNA expression and showed a tendency to inhibit elevation of LOX-1 mRNA expression. Pravastatin significantly prevented upregulation of both VCAM-1 and LOX-1 mRNA expression. The results demonstrate that pravastatin inhibits increase of serum cholesterol and vascular dysfunction in hypercholesterolemic rabbit. Benidipine is effective in preventing vascular hyperplasia without altering serum cholesterol levels and this may be due to inhibition of expression of VCAM-1.

Pactimibe stabilizes atherosclerotic plaque through macrophage acyl-CoA:cholesterol acyltransferase inhibition in WHHL rabbits

Novel acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor pactimibe was administered as the sulfate salt form to 3-month-old homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits at doses of 0, 10, or 30 mg/kg for 32 weeks. Pactimibe (10 and 30 mg/kg) tended to reduce intimal thickening in thoracic aortic lesions (294 ± 39 and 276 ± 32 μm, respectively, versus 313 ± 37 μm control), histopathological examination revealing significantly increased smooth muscle cell area (12.0 ± 0.9% and 12.3 ± 0.5%, P < 0.05, respectively, versus 9.7 ± 0.8% control), significantly increased collagen fiber area (20.5 ± 1.2% and 31.0 ± 1.3%, P < 0.05, respectively, versus 16.2 ± 1.0% control), and tended to reduce macrophage infiltration (6.0 ± 1.1% and 4.6 ± 1.0%, respectively, versus 7.0 ± 1.3% control). Pactimibe dose-dependently reduced cholesteryl ester content in thoracic and abdominal aortic lesions, and reduced free cholesterol content in the aorta versus control. Although pactimibe did not alter serum cholesterol levels in WHHL rabbits, it stabilized vulnerable plaque characterized with reduced cholesteryl ester content, enriched collagen fibers and increased smooth muscle cells, indicating potential as a treatment strategy for coronary heart disease.

Taurocholate Deconjugation and Cholesterol Binding by Indigenous Dadih Lactic Acid Bacteria

High serum cholesterol levels have been associated with an increased risk for human coronary heart disease. Lowering of serum cholesterol has been suggested to prevent the heart disease. To reduce serum cholesterol levels one may consumed diet supplementat of fermented dairy product such as dadih. Lactic acid bacteria present in dadih may alter serum cholesterol by directly bind to dietary cholesterol and/or deconjugation of bile salts. Acid and bile tolerance, deconjugation of sodium taurocholate, and the cholesterol-binding ability of lactic acid bacteria from dadih were examined. Among ten dadih lactic acid bacteria tested, six strains namely I-11, I-2775, K-5, I-6257, IS-7257, and B-4 could bind cholesterol and deconjugate sodium taurocholate. However, the last four strains were very sensitive to bile. Therefore, Lactobacillus fermentum I-11 and Leuconostoc lactis subsp. lactis I-2775 those were tolerant to acid and oxgall (bile) and deconjugated sodium taurocholate and bound cholesterol could be recommended as probiotic to prevent coronary heart disease.

The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L)

The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L). MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial. Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups. The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.