Hyperlipidemias: Wang X

Wang X, Paigen B. · Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA. · Circ Res. · Pubmed #15637305 links to  free full text

Abstract: Plasma high-density lipoprotein cholesterol (HDL-C) concentrations are genetically determined to a great extent, and quantitative trait locus (QTL) analysis has been used to identify chromosomal regions containing genes regulating HDL-C levels. We discuss new genes found to participate in HDL metabolism. We also summarize 37 mouse and 30 human QTLs for plasma HDL-C levels, finding that all but three of the mouse QTLs have been confirmed by a second cross or a homologous human QTL, that the mouse QTL map is almost saturated because 92% of recently reported QTLs are repeats of those already found, and that 28 of the 30 human QTLs are located in regions homologous to mouse QTLs. This high degree of concordance between mouse and human QTLs suggests that the underlying genes may be the same. Strategies to more rapidly identify genes underlying mouse and human QTLs for HDL-C include focusing on the mouse and using mouse-human homologies, combining crosses, and haplotyping to narrow the region. Sequence analysis and expression studies can distinguish candidate genes consistent across multiple mouse crosses, and testing the candidate genes in human association studies can provide additional evidence for the candidacy of a gene. Together these strategies can accelerate the pace of finding genes that regulate HDL.

Jin N, Wang X. · Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100083. · Sheng Li Ke Xue Jin Zhan. · Pubmed #15127591 No free full text.

Abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-dependant nuclear transcription factors, consisting of three isoforms: alpha,beta/delta and gamma, which form a subfamily of the nuclear receptors superfamily. PPARs play an important role in adipocyte differentiation, energy metabolism, and inflammation. PPARs' effect goes beyond the improvement of insulin resistance in syndrome X (diabetes mellitus, hypertension, obesity and so on). Through recent years' study, it has been demonstrated that PPARs regulate vascular wall directly, which, therefore, decelerate the development of atherosclerosis. In this review, we will look at current trends of PPARs research in their structure, function, and molecular mechanism related to pathogenesis and therapy of atherosclerosis.

Xie N, Wang X, Cai S. · School of Pharmaceutical Science, Beijing Medical University, Beijing 100083 · Zhong Yao Cai. · Pubmed #12920710 No free full text.

This publication has no abstract.

Li Q, Fan P, Bai H, Liu R, Huang Y, Wang X, Wu H, Liu Y, Liu B. · Unit of Laboratory Medicine, West China Second Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China. · Clin Chim Acta. · Pubmed #19239905 No free full text.

Abstract: BACKGROUND: ApoL-I is a newly found component of HDL, and has a potential role in the lipid metabolism. This study was mainly to examine the possible association of the ApoL-I gene polymorphism with endogenous hypertriglyceridemia (HTG) in Chinese population. METHODS: Three hundred and thirty five Han Chinese (102 HTG and 233 healthy control subjects) in Chengdu area were studied using PCR-RFLP analysis. RESULTS: The Lys and Glu allele frequencies of apoL-I gene at Lys166Glu site in HTG and normal control groups were 0.857, 0.143 and 0.801, 0.199, respectively; The Ile and Met allele frequencies of the gene at Ile244Met site in HTG and the control groups were 0.868, 0.132 and 0.812, 0.188 respectively. The 166Glu and 244Met allele frequencies of the 2 polymorphisms in HTG subjects were not different from those in the normal controls, respectively (P>0.05). In HTG group, subjects with genotype Lys/lys of Lys166Glu site had a higher serum mean concentration of TG as compared to those of Glu allele carriers (3.64+/-1.55 mmol/l vs 2.86+/-0.51 mmol/l, P<0.05). Subjects with genotype Ile/Ile of Ile244Met site had a higher serum mean concentration of TG as compared to those of Met allele carriers (3.59+/-1.56 mmol/l vs 2.94+/-0.88 mmol/l, P<0.05). CONCLUSIONS: The Lys166Glu and Ile244Met polymorphisms in apoL-I gene are associated with TG levels in subjects with endogenous hypertriglyceridemia in Chinese. However, these polymorphisms were not associated with the risk of HTG in the population.

Bennett BJ, Wang SS, Wang X, Wu X, Lusis AJ. · Department of Medicine, 675 Charles E. Young Dr South, 3730 MRL, School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1679, USA. · Arterioscler Thromb Vasc Biol. · Pubmed #19122174 No free full text.

Abstract: OBJECTIVE: We sought to determine the genetic factors contributing to atherosclerotic plaque size and cellular composition in the innominate artery, a murine model of advanced atherosclerosis. METHODS AND RESULTS: We examined genetic contributions to innominate atherosclerotic plaque size and cellular composition in an intercross between C57BL/6J.Apoe(-/-), a strain susceptible to aortic lesions, and C3H/HeJ.Apoe(-/-), a strain resistant to aortic lesions. Surprisingly, total innominate lesion size was similar in the two strains. Genetic analyses identified one novel locus on Chromosome 2 for innominate artery lesion size, a significant locus for fibrous cap thickness on Chromosome 15, and several suggestive loci for cellular composition, all distinct from loci influencing aortic lesions. The Chromosome 2 locus contains a candidate, CD44. We show that CD44 is expressed in the innominate artery and differs strikingly in expression between the parental strains. CONCLUSION: Multiple aspects of innominate lesion composition are genetically determined, but in a manner largely independent of the genetic contributions to aortic lesions.

Ma KW, Ma L, Cai SX, Wang X, Liu B, Xu ZL, Dai XZ, Yang JY, Jing AH, Lei WJ. · College of Medical Technology & Engineering, Henan University of Science and Technology, Luoyang 471003, People's Republic of China. · J Mater Sci Mater Med. · Pubmed #18470702 No free full text.

Abstract: In this study, heparin was covalently coupled by glutaraldehyde to Poly(vinyl alcohol) [PVA] in solid-liquid two-phase reaction system by two-step synthesis method to prepare a LDL-selective adsorbent. The parameters (the material ratio, reaction time and dosage of catalyzer) were investigated to evaluate their effect upon the immobilized amount of heparin onto the surface of PVA, IR was used to verify the covalent immobilization result and the heparin-modified PVA was also undergone the evaluation of its adsorption capability for low-density lipoprotein from hyperlipemia plasma, and its hemocompatibility was preliminarily evaluated by platelet adhesion test. Results showed: (1) under optimized reaction conditions the highest immobilization amount of heparin onto PVA surface within the experiments of this study has been obtained; (2) the optimized reaction conditions were: (i) at the refluxing temperature 78 degrees C; (ii) the material ratio of "PVA(g): 50% glutaraldehyde (ml)" was about "1:3"; (iii) the reaction time was about 5 h; and (iv) the amount of catalyzer (concentrated HCL) was about 1% of the 50% glutaraldehyde; (3) within the experiments of this study the highest immobilization amount would be up to 25 microg heparin on the surface of per g PVA granules; (4) the heparin-modified PVA granules showed significant adsorption for LDL under faintly alkaline environment (pH=7.2-9.5) ; (5) The result of platelet adhesion test showed no platelet adhered to its surface. Therefore, immobilization of heparin onto the surface of a support is one approach to prepare a kind of LDL adsorbent for blood purification.

Zhang W, Wang X, Liu Y, Tian H, Flickinger B, Empie MW, Sun SZ. · Tumor Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Br J Nutr. · Pubmed #18053310 No free full text.

Abstract: Lignans, derived from flaxseed, are phyto-oestrogens being increasingly studied for their health benefits. An 8-week, randomised, double-blind, placebo-controlled study was conducted in fifty-five hypercholesterolaemic subjects, using treatments of 0 (placebo), 300 or 600 mg/d of dietary secoisolariciresinol diglucoside (SDG) from flaxseed extract to determine the effect on plasma lipids and fasting glucose levels. Significant treatment effects were achieved (P < 0.05 to < 0.001) for the decrease of total cholesterol (TC), LDL-cholesterol (LDL-C) and glucose concentrations, as well as their percentage decrease from baseline. At weeks 6 and 8 in the 600 mg SDG group, the decreases of TC and LDL-C concentrations were in the range from 22.0 to 24.38 % respectively (all P < 0.005 compared with placebo). For the 300 mg SDG group, only significant differences from baseline were observed for decreases of TC and LDL-C. A substantial effect on lowering concentrations of fasting plasma glucose was also noted in the 600 mg SDG group at weeks 6 and 8, especially in the subjects with baseline glucose concentrations > or = 5.83 mmol/l (lowered 25.56 and 24.96 %; P = 0.015 and P = 0.012 compared with placebo, respectively). Plasma concentrations of secoisolariciresinol (SECO), enterodiol (ED) and enterolactone were all significantly raised in the groups supplemented with flaxseed lignan. The observed cholesterol-lowering values were correlated with the concentrations of plasma SECO and ED (r 0.128-0.302; P < 0.05 to < 0.001). In conclusion, dietary flaxseed lignan extract decreased plasma cholesterol and glucose concentrations in a dose-dependent manner.

Lipson AH, Fallis WM, Wang X, Yi Y. · Victoria General Hospital, 2340 Pembina Highway, Winnipeg, MB R3T 2E8, Canada. · Can Fam Physician. · Pubmed #17872880 links to  free full text

Abstract: OBJECTIVE: To identify patients admitted to hospital with coronary events and to estimate their pre-admission coronary risk, including their lipid levels. Despite the available data and numerous guidelines, evidence indicates that many patients with hyperlipidemia are undertreated and are not achieving target lipid levels. DESIGN: Retrospective chart review. SETTING: Acute care community hospital in Winnipeg, Man. PARTICIPANTS: A total of 153 patients who were diagnosed with acute myocardial infarction, unstable angina, or acute coronary syndrome upon admission. METHOD: Each patient's 10-year risk of developing coronary artery disease was calculated, and his or her risk status was established. Each patient's low-density lipoprotein cholesterol (LDL-C) levels were recorded and categorized based on current Canadian guidelines. RESULTS: Mean age of patients was 67.6 years; 60.8% were male. Patients in the low-risk category had a mean LDL-C level of 2.98 mmol/L (95% confidence interval [CI] 2.66 to 3.29), and patients in the moderate-risk category had a mean LDL-C level of 3.01 mmol/L (95% CI 2.74 to 3.28), both significantly lower (P < .05) than the LDL-C target levels for patients in those risk categories according to Canadian guidelines. The mean LDL-C level for patients in the very high-risk category, however, was 2.53 mmol/L (95% CI 2.35 to 2.71), above the recommended goal. Almost half the patients (48.3%) in the very high-risk category had LDL-C levels that exceeded the goal. Slightly more than 1 in 3 patients in the very high-risk category was reported to be taking lipid-lowering agents. CONCLUSION: Patients in the community who are at very high risk of having cardiovascular events are undertreated with respect to attaining LDL-C target levels. These findings point to an opportunity to prevent patient morbidity and reduce the number of hospitalizations for cardiovascular events.

Bradley MN, Hong C, Chen M, Joseph SB, Wilpitz DC, Wang X, Lusis AJ, Collins A, Hseuh WA, Collins JL, Tangirala RK, Tontonoz P. · Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, California 90095-1662, USA. · J Clin Invest. · Pubmed #17657314 links to  free full text

Abstract: Liver X receptors (LXRs) alpha and beta are transcriptional regulators of cholesterol homeostasis and potential targets for the development of antiatherosclerosis drugs. However, the specific roles of individual LXR isotypes in atherosclerosis and the pharmacological effects of synthetic agonists remain unclear. Previous work has shown that mice lacking LXRalpha accumulate cholesterol in the liver but not in peripheral tissues. In striking contrast, we demonstrate here that LXRalpha(-/-)apoE(-/-) mice exhibit extreme cholesterol accumulation in peripheral tissues, a dramatic increase in whole-body cholesterol burden, and accelerated atherosclerosis. The phenotype of these mice suggests that the level of LXR pathway activation in macrophages achieved by LXRbeta and endogenous ligand is unable to maintain homeostasis in the setting of hypercholesterolemia. Surprisingly, however, a highly efficacious synthetic agonist was able to compensate for the loss of LXRalpha. Treatment of LXRalpha(-/-)apoE(-/-) mice with synthetic LXR ligand ameliorates the cholesterol overload phenotype and reduces atherosclerosis. These observations indicate that LXRalpha has an essential role in maintaining peripheral cholesterol homeostasis in the context of hypercholesterolemia and provide in vivo support for drug development strategies targeting LXRbeta.

Wang SS, Schadt EE, Wang H, Wang X, Ingram-Drake L, Shi W, Drake TA, Lusis AJ. · Department of Human Genetics, University of California at Los Angeles, Los Angeles, CA 90095-1679, USA. · Circ Res. · Pubmed #17641228 links to  free full text

Abstract: We report a combined genetic and genomic analysis of atherosclerosis in a cross between the strains C3H/HeJ and C57BL/6J on a hyperlipidemic apolipoprotein E-null background. We incorporated sex and sex-by-genotype interactions into our model selection procedure to identify 10 quantitative trait loci for lesion size, revealing a level of complexity greater than previously thought. Of the known risk factors for atherosclerosis, plasma triglyceride levels and plasma glucose to insulin ratios were particularly strongly, but negatively, associated with lesion size. We performed expression array analysis for 23,574 transcripts of the livers and adipose tissues of all 334 F2 mice and identified more than 10,000 expression quantitative trait loci that either mapped to the gene encoding the transcript, implying cis regulation, or to a separate locus, implying trans-regulation. The gene expression data allowed us to identify candidate genes that mapped to the atherosclerosis quantitative trait loci and for which the expression was regulated in cis. Genes highly correlated with lesions were enriched in certain known pathways involved in lesion development, including cholesterol metabolism, mitochondrial oxidative phosphorylation, and inflammation. Thus, global gene expression in peripheral tissues can reflect the systemic perturbations that contribute to atherosclerosis.

Hattori Y, Hattori S, Wang X, Satoh H, Nakanishi N, Kasai K. · Department of Endocrinology & Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. · Arterioscler Thromb Vasc Biol. · Pubmed #17272747 links to  free full text

Abstract: OBJECTIVE: Although it has been reported that oral administration of tetrahydrobiopterin (BH4) prevents endothelial dysfunction and vascular oxidative stress in various rat models, the effect of treatment with BH4 on atherogenesis remains unclear. METHODS AND RESULTS: In this study, we investigated whether oral BH4 treatment might slow the progression of atherosclerosis using hypercholesterolemic apolipoprotein E-knockout mice. We report that ingesting BH4 in drinking water is sufficient to inhibit atherogenesis in mice. Furthermore, we report that BH4 treatment improves endothelial dysfunction and attenuates increased mRNA expression of NADPH oxidase components, as well as a number of inflammatory factors, such as LOX-1 and MCP-1, in the aortas of apolipoprotein E- knockout mice. CONCLUSION: Strategies such as oral administration of BH4 to ensure continuous BH4 availability may be effective in restoring nitric oxide-mediated endothelial function and limiting vascular disease and the progression of atherosclerosis.

Lewis JD, Schinnar R, Bilker WB, Wang X, Strom BL. · Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA. · Pharmacoepidemiol Drug Saf. · Pubmed #17066486 No free full text.

Abstract: BACKGROUND: The Health Improvement Network (THIN) is a new medical records database that contains records from general practices some of which have or continue to participate in the General Practice Research Database (GPRD) and others that never participated in GPRD. We sought to replicate in THIN well-established associations from the medical literature and to compare results from the GPRD practices to the non-GPRD practices within THIN. METHODS: Using THIN data from 1986-2003, we conducted case-control studies of associations between diseases (e.g., hypertension and stroke) and between diseases and drugs (e.g., aspirin and colon cancer). Conditional logistic regression was used to calculate odds ratios adjusted for potential confounders. Differences between GPRD and non-GPRD practices were assessed by testing for a statistical interaction by practice type in each outcome-exposure association. RESULTS: We observed the expected positive associations (p < 0.05) of stroke with hypertension and diabetes mellitus; of myocardial infarction with hypertension, hypercholesterolemia, obesity, and smoking; and of peptic ulcer disease with aspirin, NSAIDs, and potassium. We observed the expected negative associations (p < 0.05) of colorectal cancer with aspirin, NSAIDs, and cox-2 inhibitors. The expected protective effect of aspirin use for myocardial infarction was not observed. In all cases, the results obtained from the GPRD practices were similar to the results obtained from the non-GPRD practices, only being statistically different for the associations of myocardial infarction with diabetes and aspirin use. CONCLUSIONS: THIN data that are collected outside of the GPRD appear as valid as the data collected as part of the GPRD.

Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. · Dermatology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · J Am Acad Dermatol. · Pubmed #17052489 No free full text.

Abstract: BACKGROUND: Previous studies suggest that patients hospitalized for psoriasis have an increased frequency of a variety of cardiovascular comorbidities. Limited population-based data exist on this association, and few studies have determined which factors are independently associated with psoriasis. OBJECTIVE: We sought to determine whether the prevalence of the major cardiovascular risk factors was higher in mild and severe psoriasis than in patients without psoriasis. METHODS: We conducted a population-based study in the United Kingdom using the General Practice Research Database. Patients were classified as having severe psoriasis if they received a code for psoriasis as well as systemic therapy. Patients were defined as having mild psoriasis if they ever received a psoriasis code but no systemic therapy. Control subjects were selected from the same practices and start dates as psoriasis patients. Patients were classified as having risk factors if they received codes for diabetes, hypertension, hyperlipidemia, obesity, or smoking. Analyses were performed by using conditional logistic regression, and adjustments were made considering age, gender, person-years, and all cardiovascular risk factors. RESULTS: We identified 127,706 patients with mild psoriasis and 3854 with severe psoriasis. Respective prevalence rates of risk factors in those with severe psoriasis, mild psoriasis, and in controls were as follows: diabetes (7.1%, 4.4%, 3.3%), hypertension (20%, 14.7%, 11.9%), hyperlipidemia (6%, 4.7%, 3.3%), obesity (20.7%, 15.8%, 13.2%), and smoking (30.1%, 28%, 21.3%). Patients with mild psoriasis had a higher adjusted odds of diabetes (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.08-1.18]), hypertension (OR, 1.03; 95% CI, 1.01-1.06), hyperlipidemia (OR, 1.16; 95% CI, 1.12-1.21), obesity (OR, 1.27; 95% CI, 1.24-1.31), and smoking (OR, 1.31; 95% CI, 1.29-1.34) than controls. Patients with severe psoriasis had a higher adjusted odds of diabetes (OR, 1.62; 95% CI, 1.3-2.01), obesity (OR, 1.79; 95% CI, 1.55-2.05), and smoking (OR, 1.31; 95% CI, 1.17-1.47) than controls. Additionally, diabetes (OR, 1.39; 95% CI, 1.22-1.58) and obesity (OR, 1.47; 95% CI, 1.32-1.63) were more prevalent in those with severe psoriasis than with mild psoriasis. LIMITATIONS: The study was cross-sectional and therefore the directionality of the associations could not be determined. CONCLUSION: Multiple cardiovascular risk factors are associated with psoriasis. Cardiovascular risk factors that are key components of the metabolic syndrome are more strongly associated with severe psoriasis than with mild psoriasis.

Wei J, Ma C, Wang X. · Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, PR China. · Biomed Res. · Pubmed #16971767 links to  free full text

Abstract: Tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) activity and/or expression are upregulated in hypercholesterolemia. Despite extensive research on anti-thrombotic effect of statins, little is known about their effects on TF and PAI-1 expression in glomerular mesangial cells under hypercholesterolemic condition. Male rabbits were fed on either normal or high-cholesterol diet for 8 weeks. Then cholesterol-fed rabbits were randomly assigned to simvastatin or starch. At the end of 12 weeks, glomerular mesangial cells were collected. The concentrations of TF and PAI-1 mRNA were detected by RT-PCR. The plasma activities of TF and PAI-1 were determined with enzyme linked immunosorbent assay (ELISA) and chromogenic substrate method, respectively. The atherogenic diet caused a consistent increase in serum concentrations of total cholesterol (TC) and serum triglyceride (TG) (p < 0.05), increased TF and PAI-1 mRNA expression in glomerular mesangial cells and plasma activities as compared to the normal diet (p < 0.01). Four-week simvastatin treatment resulted in significant decrease of mesangial TF and PAI-1 mRNA (p < 0.01), and also of the plasma activities of TF (p < 0.05) and PAI-1 (p < 0.01). These results suggest that simvastatin might protect kidney from the formation of microthrombus under hypercholesterolemic condition and might be a possible pathogenesis of obesity-related glomerulopathy.

Zeggini E, Damcott CM, Hanson RL, Karim MA, Rayner NW, Groves CJ, Baier LJ, Hale TC, Hattersley AT, Hitman GA, Hunt SE, Knowler WC, Mitchell BD, Ng MC, O'Connell JR, Pollin TI, Vaxillaire M, Walker M, Wang X, Whittaker P, Xiang K, Kunsun X, Jia W, Chan JC, Froguel P, Deloukas P, Shuldiner AR, Elbein SC, McCarthy MI, Anonymous00120. · Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. · Diabetes. · Pubmed #16936202 links to  free full text

Abstract: The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits.

Estrada-Smith D, Collins AR, Wang X, Crockett C, Castellani L, Lusis AJ, Davis RC. · Department of Human Gentics, University of California Los Angeles, USA. · Diabetes. · Pubmed #16873689 links to  free full text

Abstract: Previous characterization of mouse chromosome 2 identified genomic intervals that influence obesity, insulin resistance, and dyslipidemia. For this, resistant CAST/Ei (CAST) alleles were introgressed onto a susceptible C57BL/6J background to generate congenic strains with CAST alleles encompassing 67-162 Mb (multigenic obesity 6 [MOB6]) and 84-180 Mb (MOB5) from mouse chromosome 2. To examine the effects of each congenic locus on atherosclerosis and glucose disposal, we bred each strain onto a sensitizing LDL receptor-null (LDLR(-/-)) C57BL/6J background to predispose them to hypercholesterolemia and insulin resistance. LDLR(-/-) congenics and controls were characterized for measures of atherogenesis, insulin sensitivity, and obesity. We identified a genomic interval unique to the MOB6 congenic (72-84 Mb) that dramatically decreased atherosclerosis by approximately threefold and decreased insulin resistance. This region also reduced adiposity twofold. Conversely, the congenic region unique to MOB5 (162-180 Mb) increased insulin resistance but had little effect on atherosclerosis and adiposity. The MOB congenic intervals are concordant to human and rat quantitative trait loci influencing diabetes and atherosclerosis traits. Thus, our results define a strategy for studying the poorly understood interactions between diabetes and atherosclerosis and for identifying genes underlying the cardiovascular complications of insulin resistance.

Xi L, Ghosh S, Wang X, Das A, Anderson FP, Kukreja RC. · Division of Cardiology, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298, USA. · Mol Cell Biochem. · Pubmed #16718361 No free full text.

Abstract: Hypercholesterolemia (HCL) is commonly associated with impaired vascular relaxation response and augmented vasoconstriction. Interestingly, it was shown that animals with HCL were less vulnerable to seizures and several clinical studies also revealed a better outcome after stroke in the patients with HCL. To this context, the present study was designed to test the hypothesis that HCL would enhance the animals' resistance to severe systemic hypoxia and in turn prolong their survival time under such noxious condition. Four groups of middle-aged (mean age: 51.1 +/- 2.8 weeks) male C57BL/6J wild-type mice (C57BL-WT) and low-density lipoprotein receptor knockout mice (LDLR-KO) were included in the study: two groups were exposed to severe normobaric hypoxia (5% F(I)O(2)) and other two groups were used for brain tissue sample collection and Western blot analysis. The survival time under the hypoxic condition was recorded for each animal. Individual blood samples were collected immedtately after the cessation of spontaneous breathing for measuring plasma total cholesterol (TCL) and triglycerides. The results show that the hypoxia survival time was longer in LDLR-KO than C57BL-WT (i.e. 3.7 +/- 0.5 versus 2.3 +/- 0.2 min; P < 0.05). A positive correlation was found between TCL and the survival time (r (2) = 0.43; P < 0.05). Furthermore, a significant downregulation of vascular endothelial growth factor (VEGF) was observed in the brain tissue of LDLR-KO, as compared with C57BL-WT (n, = 3/group; P < 0.05), whereas expression of heme oxygenase 1 was similar in these two groups. We conclude that HCL enhances resistance to lethal systemic hypoxia (i.e. 61% increase in survival time) in middle-aged mice. This paradoxical protective effect of HCL was associated with a concomitant downregulation of cerebral VEGF expression, which could potentially blunt the hypoxia-triggered and VEGF-mediated pathophysiological events leading to death.

Castellani LW, Chang JJ, Wang X, Lusis AJ, Reynolds WF. · Department of Medicine, University of California-Los Angeles, 90095, USA. · J Lipid Res. · Pubmed #16639078 links to  free full text

Abstract: Myeloperoxidase (MPO) is an oxidant-generating enzyme present in macrophages at atherosclerotic lesions and implicated in coronary artery disease (CAD). Although mouse models are important for investigating the role of MPO in atherosclerosis, neither mouse MPO nor its oxidation products are detected in lesions in murine models. To circumvent this problem, we generated transgenic mice expressing two functionally different human MPO alleles, with either G or A at position -463, and crossed these to the LDL receptor-deficient (LDLR(-/-)) mouse. The -463G allele is linked to higher MPO expression and increased CAD incidence in humans. Both MPO alleles were expressed in a subset of lesions in high-fat-fed LDLR(-/-) mice, notably at necrotic lesions with cholesterol clefts. MPOG-expressing LDLR(-/-) males (but not females) developed significantly higher serum cholesterol, triglycerides, and glucose, all correlating with increased weight gain/obesity, implicating MPO in lipid homeostasis. The MPOG- and MPOA-expressing LDLR(-/-) males also exhibited significantly larger aortic lesions than control LDLR(-/-) males. The human MPO transgenic model will facilitate studies of MPO involvement in atherosclerosis and lipid homeostasis.

Koike T, Liang J, Wang X, Ichikawa T, Shiomi M, Sun H, Watanabe T, Liu G, Fan J. · Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan. · Cardiovasc Res. · Pubmed #15639492 links to  free full text

Abstract: OBJECTIVE: This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency. METHODS: We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits. RESULTS: Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006-1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04-1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits. CONCLUSIONS: We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.

Wang X, Gargalovic P, Wong J, Gu JL, Wu X, Qi H, Wen P, Xi L, Tan B, Gogliotti R, Castellani LW, Chatterjee A, Lusis AJ. · Department of Medicine,University of California, Los Angeles 90095-1679, USA. · Arterioscler Thromb Vasc Biol. · Pubmed #15331434 links to  free full text

Abstract: OBJECTIVE: We previously reported the mapping of a quantitative trait locus (QTL) on chromosome 15 contributing to hyperlipidemia in a cross between inbred strains MRL/MpJ (MRL) and BALB/cJ (BALB). Using marker-assisted breeding, we constructed a congenic strain in which chromosome 15 interval from MRL is placed on the genetic background of BALB. The congenic allowed us to confirm the QTL result and to further characterize the properties and location of the underlying gene. METHODS AND RESULTS: On chow and high-fat (atherogenic) diets, the congenic mice exhibited higher levels of plasma triglycerides and cholesterol than BALB mice. In response to the atherogenic diet, the congenic mice but not BALB mice exhibited a dramatic approximately 30-fold increase in atherogenic lesions accompanied by approximately 2-fold decrease in high-density lipoprotein cholesterol levels. With respect to atherosclerotic lesions and some lipid parameters, this chromosome 15 gene, designated Hyplip2, exhibited dominant inheritance. Expression array analyses suggested that Hyplip2 may influence inflammatory and bile acid synthesis pathways. Finally, we demonstrated the usefulness of subcongenic strains to narrow the locus (50 Mbp) with the goal of positionally cloning Hyplip2. CONCLUSIONS: Our data demonstrate that the Hyplip2 gene significantly contributes to combined hyperlipidemia and increased atherosclerosis in mice.

Shi W, Wang X, Wong J, Hedrick CC, Wong H, Castellani LW, Lusis AJ. · Department of Radiology, University of Virginia, Charlottesville 22908, USA. · Biochem Biophys Res Commun. · Pubmed #15047172 No free full text.

Abstract: LDL receptor-deficient (LDLR(-/-)) mice fed a Western diet exhibit severe hyperlipidemia and develop significant atherosclerosis. Apolipoprotein E (apoE) is a multifunctional protein synthesized by hepatocytes and macrophages. We sought to determine effect of macrophage apoE deficiency on severe hyperlipidemia and atherosclerosis. Female LDLR(-/-) mice were lethally irradiated and reconstituted with bone marrow from either apoE(-/-) or apoE(+/+) mice. Four weeks after transplantation, recipient mice were fed a Western diet for 8 weeks. Reconstitution of LDLR(-/-) mice with apoE(-/-) bone marrow resulted in a slight reduction in plasma apoE levels and a dramatic reduction in accumulation of apoE and apoB in the aortic wall. Plasma lipid levels were unaffected when mice had mild hyperlipidemia on a chow diet, whereas IDL/LDL cholesterol levels were significantly reduced when mice developed severe hyperlipidemia on the Western diet. The hepatic VLDL production rate of mice on the Western diet was decreased by 46% as determined by injection of Triton WR1339 to block VLDL clearance. Atherosclerotic lesions in the proximal aorta were significantly reduced, partially due to reduction in plasma total cholesterol levels (r=0.56; P<0.0001). Thus, macrophage apoE-deficiency alleviates severe hyperlipidemia by slowing hepatic VLDL production and consequently reduces atherosclerosis in LDLR(-/-) mice.

Koike T, Liang J, Wang X, Ichikawa T, Shiomi M, Liu G, Sun H, Kitajima S, Morimoto M, Watanabe T, Yamada N, Fan J. · Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan. · J Biol Chem. · Pubmed #14660566 links to  free full text

Abstract: Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of the triglyceride-rich lipoproteins and plays a critical role in lipoprotein and free fatty acid metabolism. Genetic manipulation of LPL may be beneficial in the treatment of hypertriglyceridemias, but it is unknown whether increased LPL activity may be effective in lowering plasma cholesterol and improving insulin resistance in familial hypercholesterolemic patients. To test the hypothesis that stimulation of LPL expression may be used as an adjunctive therapy for treatment of homozygous familial hypercholesterolemia, we have generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits that overexpress the human LPL transgene and compared their plasma lipid levels, glucose metabolism, and body fat accumulation with those of non-Tg WHHL rabbits. Overexpression of LPL dramatically ameliorated hypertriglyceridemia in Tg WHHL rabbits. Furthermore, increased LPL activity in male Tg WHHL rabbits also corrected hypercholesterolemia (544 +/- 52 in non-Tg versus 227 +/- 29 mg/dl in Tg, p < 0.01) and reduced body fat accumulation by 61% (323 +/- 27 in non-Tg versus 125 +/- 21ginTg, p < 0.01), suggesting that LPL plays an important role in mediating plasma cholesterol homeostasis and adipose accumulation. In addition, overexpression of LPL significantly suppressed high fat diet-induced obesity and insulin resistance in Tg WHHL rabbits. These results imply that systemic elevation of LPL expression may be potentially useful for the treatment of hyperlipidemias, obesity, and insulin resistance.

Tu Z, Han X, Wang X, Hou Y, Shao B, Wang X, Zhou Q, Fan Q. · Reproductive Immunology Laboratory, Nanjing University Medical School, Nanjing, Jiangsu 210093, PR China. · Clin Chim Acta. · Pubmed #12809739 No free full text.

Abstract: BACKGROUND: The cardiovascular protective mixture (CVPM) is a concoction of nine Chinese traditional medicines: Dan-shen root, Szechwan lovge rhizome, Chinese angelica, Hawthorn fruit, Safflower, Peach seed, Red peony root, earthworm, and membranous milkvetch root. These medicines are used to cure cardiovascular disease in China. METHODS: Animal models were established by feeding the Sprague-Dawley (SD) rats with lipid-rich forage. Serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were measured. Malondialdehyde (MDA) content was determined to monitor lipid peroxidation. The 6-keto-prostaglandin F(1alpha)(6-keto-PGF(1alpha)) concentration was measured by radioimmunoassay to investigate the content of prostacyclin (PGI(2)). Electron microscope (JEM-1200EX) was used to observe the microstructure of the vascular endothelium. Rat aortic endothelial cell was cultured to investigate the effect of CVPM on vascular endothelial cell in vitro. RESULTS: CVPM inhibited the accumulation of TC, LDL-C, and MDA in vivo, when the rats were fed with cholesterol diet. CVPM promoted synthesizing and excreting of PGI(2), since it is capable of activating the proliferation of vascular endothelium in vitro. Electron micrographs showed that CVPM had notable protective effect on the vascular endothelium and prevented the shedding of these cells from subendothelial layer. CONCLUSIONS: CVPM could ameliorate the internal environment in which vascular endothelial cells lived, and activate the proliferation of these cells. Through these mechanisms, CVPM protect vascular endothelial cell from being harmed by excess cholesterol in vivo.

Tu Z, Han X, Wang X, Hou Y, Shao B, Wang X, Zhou Q, Fan Q. · Reproductive Immunology Laboratory, Nanjing University Medical School, Nanjing, Jiangsu 210093, PR China. · Clin Chim Acta. · Pubmed #12809739 No free full text.

Abstract: BACKGROUND: The cardiovascular protective mixture (CVPM) is a concoction of nine Chinese traditional medicines: Dan-shen root, Szechwan lovge rhizome, Chinese angelica, Hawthorn fruit, Safflower, Peach seed, Red peony root, earthworm, and membranous milkvetch root. These medicines are used to cure cardiovascular disease in China. METHODS: Animal models were established by feeding the Sprague-Dawley (SD) rats with lipid-rich forage. Serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were measured. Malondialdehyde (MDA) content was determined to monitor lipid peroxidation. The 6-keto-prostaglandin F(1alpha)(6-keto-PGF(1alpha)) concentration was measured by radioimmunoassay to investigate the content of prostacyclin (PGI(2)). Electron microscope (JEM-1200EX) was used to observe the microstructure of the vascular endothelium. Rat aortic endothelial cell was cultured to investigate the effect of CVPM on vascular endothelial cell in vitro. RESULTS: CVPM inhibited the accumulation of TC, LDL-C, and MDA in vivo, when the rats were fed with cholesterol diet. CVPM promoted synthesizing and excreting of PGI(2), since it is capable of activating the proliferation of vascular endothelium in vitro. Electron micrographs showed that CVPM had notable protective effect on the vascular endothelium and prevented the shedding of these cells from subendothelial layer. CONCLUSIONS: CVPM could ameliorate the internal environment in which vascular endothelial cells lived, and activate the proliferation of these cells. Through these mechanisms, CVPM protect vascular endothelial cell from being harmed by excess cholesterol in vivo.

Sun H, Unoki H, Wang X, Liang J, Ichikawa T, Arai Y, Shiomi M, Marcovina SM, Watanabe T, Fan J. · Laboratory of Cardiovascular Disease, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan. · J Biol Chem. · Pubmed #12196525 links to  free full text

Abstract: High lipoprotein(a) (Lp(a)) levels are a major risk factor for the development of atherosclerosis. The risk of elevated Lp(a) concentration is increased significantly in patients who also have high levels of low density lipoprotein (LDL) cholesterol. To test the hypothesis that increased plasma levels of Lp(a) may enhance the development of atherosclerosis in the setting of hypercholesterolemia, we generated Watanabe heritable hyperlipidemic (WHHL) transgenic (Tg) rabbits expressing human apolipoprotein(a) (apo(a)). We report here that Tg WHHL rabbits developed more extensive advanced atherosclerotic lesions than did non-Tg WHHL rabbits. In particular, the advanced atherosclerotic lesions in Tg WHHL rabbits were frequently associated with calcification, which was barely evident in non-Tg WHHL rabbits. To investigate the molecular mechanism of Lp(a)-induced vascular calcification, we examined the effect of human Lp(a) on cultured rabbit aortic smooth muscle cells and found that smooth muscle cells treated with Lp(a) showed increased alkaline phosphatase activity and enhanced calcium accumulation. These results demonstrate for the first time that Lp(a) accelerates advanced atherosclerotic lesion formation and may play an important role in vascular calcification.