Nuclear receptors are transcription factors that can be activated by specific ligands. Recent progress has shown that retinoid X receptor (RXR) and its heterodimerization partners, including peroxisome proliferator-activated receptors, regulate many important genes involved in energy homeostasis and atherosclerosis, and should be promising therapeutic targets of metabolic syndrome. RXR heterodimers regulate a number of complex cellular processes, and genetic studies of RXR heterodimers have provided important clinical information in addition to knowledge gained from basic research. Genetic variants of RXR heterodimers were screened and investigated, and some variants were shown to have a considerable impact on metabolic disorders, including phenotypic components of familial combined hyperlipidemia. The combined efforts of basic and clinical science regarding nuclear receptors have achieved significant progress in unraveling the inextricably linked control system of energy expenditure, lipid and glucose homeostasis, inflammation, and atherosclerosis.
This review summarizes the current understanding regarding RXR heterodimers based on their human genetic variants, which will provide new clues to uncover the background of multifactorial disease, such as metabolic syndrome or familial combined hyperlipidemia.

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Aim: To investigate the mechanisms underlying the pro-angiogenic effects of statin, the effects of atorvastatin were investigated on the expression of angiogenic factors in ischemic hindlimbs of rats. The function and number of endothelial progenitor cells (EPCs) were investigated in hypertensive rats.
Methods: Hindlimb ischemia rats were administered 10 or 30 mg/kg/day atorvastatin orally for 2 weeks. Angiogenesis was evaluated by a laser Doppler and by Isolectin-B4 immunostaining. The expressions of VEGF, IL-8, angiopoietin (Ang)-1, Ang-2, eNOS, and hemoxidase (HO)-1 were evaluated by Western blotting and immunohistochemistry. Spontaneously hypertensive rats (SHR) were administered 10 mg/kg/day atorvastatin. EPC function was evaluated by colony formation and migration. The EPC number was evaluated by CD34-positive cells.
Results: A lowdose of atorvastatin, but not a highdose, significantly increased regional blood flow. Atorvastatin significantly increased the expressions of VEGF, IL-8, Ang-1, Ang-2, eNOS, and HO-1 proteins in ischemic hindlimbs. Atorvastatin significantly increased the number and colony formation of EPCs and decreased oxidation in mononuclear cells from SHR.
Conclusion: Atorvastatin strongly induced angiogenesis with increases in angiogenic cytokines, HO-1 and EPC numbers. Statins are thus considered potertial agents for therapeutic angiogenesis.

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Aim: Hypertriglyceridemia is the most common cause of low plasma high-density lipoprotein cholesterol (HDL-C) levels; however, the correlation between high triglyceride (TG) and low HDL-C remains unclear. Endothelial lipase (EL) is a determinant of plasma HDL levels. We investigated the role of EL in HDL metabolism in a murine model of acute hypertriglyceridemia.
Methods and Results: To establish TG-dominant hyperlipidemia, EL-/- and wild-type (WT) mice were injected with Poloxamer-407 (P-407, 0.5 g/kg, i.p.). A single injection of P-407 resulted in a marked increase in plasma TG and cholesterol levels together with a decrease in HDL-C levels. Although plasma TG levels were similar in EL-/- and WT mice after P-407 injection, HDL-C levels were 80% higher and the HDL particle size was significantly larger in EL-/- mice than in WT mice. P-407 treatment inhibited plasma lipoprotein lipase activity and EL phospholipase activity, without decreasing their expressions. Adenovirus-mediated overexpression of EL in the liver reduced plasma HDL-C levels in both normo- and hyperlipidemic mice, while overexpression of catalytically inactive EL reduced HDL-C levels in hyperlipidemic mice. Cell culture experiments revealed that both catalytically active and inactive EL promoted cellular HDL uptake to the same extent.
Conclusion: EL regulates plasma HDL levels in mice in the normolipidemic as well as the acute hypertriglyceridemic state. EL can modulate plasma HDL-CHOL levels through both its lipolytic and ligand-binding functions in hypertriglyceridemic mice, while lipolytic activity appears to be the main determinant for its effects on HDL metabolism in normolipidemic mice.

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Aim: E-selectin and C-reactive protein have been linked with carotid atherosclerosis; however, the findings on this association have been inconsistent.
Methods and Results: We conducted a cross-sectional study to examine the associations of soluble E-selectin (sE-selectin) and high-sensitivity-CRP (hs-CRP) levels with carotid intima-media thickness (IMT) in 505 Japanese men aged 6074 years. Maximum IMT of common (CCA) and internal carotid arteries (ICA) was positively associated with sE-selectin levels after adjustment for age, hs-CRP and other cardiovascular risk factors: means of maximum CCA IMT were 1.12, 1.21 and 1.27 mm for the lowest to highest tertiles of sE-selectin, respectively, p=0.04, and those of ICA IMT were 1.73, 2.09 and 2.09 mm, respectively, p=0.009. Maximum IMT of CCA tended to be positively associated hs-CRP levels after adjustment for age, sE-selectin and other cardiovascular risk factors: means of maximum CCA IMT were 1.10, 1.25, and 1.26 mm, for the lowest to highest tertiles of hs-CRP, respectively, p=0.06. Compared with subjects with the lowest tertiles of sE-selectin and hs-CRP, those with the highest tertiles had a higher prevalence of heterogeneous plaque: multivariable odds ratios were 2.2 (1.03.7), p=0.002 and 1.6 (1.02.7), p=0.046, respectively.
Conclusions: Serum levels of sE-selectin and hs-CRP could be biomarkers for atherosclerosis in general populations.

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Aim: Vascular or valvular calcification is a manifestation of atherosclerosis. The aim of this study was to clarify the association between calcification in the vascular or valvular area and significant coronary stenosis; that is, the requirements of coronary revascularization (CR), and to analyze the most associated marker among those valuables.
Methods and Results: A total of 253 consecutive patients underwent multi-detector spiral computed tomography (MDCT) to diagnose coronary artery stenosis. We quantitatively and qualitatively analyzed calcification in vascular (coronary artery, thoracic ascending and descending aorta) and valvular (mitral and aortic valve) areas. Of 253 patients, 56 with suspected coronary artery stenosis or who had heavy calcification that precluded a diagnosis of lumen stenosis underwent selective coronary angiography. Coronary artery stenosis was significant in 47 patients, of whom 40 underwent CR. The calcification score revealed a significant association between any two sites. Univariate analysis revealed that CR patients showed significantly more calcification at sites other than the aortic valve and a significantly higher calcium score at 3 vascular beds. Multivariate analysis revealed that the presence of calcification in the ascending aorta and a calcium score > 103.8, a cut-off value determined by receiver-operating characteristics (ROC) curve analysis, for the coronary artery were independent factors for CR.
Conclusions: Calcification at sites other than the aortic valve was significantly related to CR (+). The presences of calcification in the ascending aorta and a calcium score > 103.8 for the coronary artery were independently associated with CR.

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Aim: Serum gamma-glutamyl transferase (GGT) activity changes in response to oxidative stress. Metabolic syndrome (MetS) is associated with an increased risk of major cardiovascular events. Few data are available on the association between serum GGT and the prevalence of MetS among community-dwelling individuals in Japan.
Methods: We recruited 793 men (mean age, 60±14 years), and 1,073 women (62±12 years), free from any history relating to cardiovascular disease during their annual health examination, from a single community. We performed a cross-sectional study to examine whether serum GGT was associated with MetS.
Results: The levels of most confounding characteristics varied with increasing GGT activity. After adjustment for age, smoking status, drinking status, low-density lipoprotein cholesterol, uric acid, estimated glomerular filtration rate and alanine aminotransferase, the odds ratios (95% confidence interval) for MetS increased across serum GGT tertiles (1, 2.23 (1.224.07), and 2.32 (1.184.56) in men; and 1, 1.43 (0.812.51), and 2.64 (1.504.64) in women). After additional adjustment for insulin resistance markers (immuno-reactive insulin or homoeostasis model assessment of insulin resistance index), the association was attenuated and the linear relation no longer significant in both genders. Furthermore, serum GGT was significantly associated with the presence of individual components of MetS in both genders, except for dyslipidemia in men and hypertension in women.
Conclusions: These results suggested that higher serum GGT was significantly associated with MetS and its components in the general population. This association was related with insulin resistance but was independent of other confounding factors.

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Aim: 7-Ketocholesterol concentrations can be measured in a blood sample; however, the relationship between blood 7-ketocholesterol concentrations and atherosclerotic disease is not well-known. The aim of this study was to clarify the clinical significance of serum 7-ketocholesterol concentrations (s-7KCHO) in the progression of coronary atherosclerosis.
Methods: One hundred and thirty-nine subjects with coronary artery disease (CAD, subjects with stable angina pectoris or acute myocardial infarction) and 43 subjects with normal coronary arteries were enrolled in the study. s-7KCHO was measured using gas chromatography mass spectrometry.
Results: s-7KCHO was significantly higher in subjects with CAD than in those with normal coronary arteries (normal coronary artery: 19.0±11.3 ng/mL, CAD: 32.4±23.1 ng/mL, p<0.01). Furthermore, patients with multiple vessel disease had significantly higher s-7KCHO than those with single vessel disease. Multivariate analysis revealed that s-7KCHO was an independent variable for CAD (p<0.01). In CAD subjects, the presence of acute myocardial infarction, number of affected vessels, and high sensitive C-reactive protein concentrations strongly correlated with s-7KCHO (p<0.01, <0.05, <0.05, respectively).
Conclusion: These results indicate that high s-7KCHO is closely associated with the progression of coronary atherosclerosis and inflammation.

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Aim: The aim of this study was to clarify the relationship between CAVI and serum cystatin C levels to understand the role of arterial stiffness in the presence of renal insufficiency.
Methods: We enrolled 206 consecutive patients with cardiovascular risk factors and/or coronary artery disease (CAD) in the study. Serum cystatin C, estimated glomerular filtration rate (eGFR), and plasma levels of von Willebrand factor (vWF) and plasminogen activator inhibitor (PAI-1) were measured. CAVI was determined as an index of arterial stiffness.
Results: For all patients, the mean serum cystatin C level was 0.81±0.21 mg/L and mean eGFR was 65.8±15.5 mL/min per 1.73 m². In univariate analysis, CAVI levels significantly correlated with cystatin C levels (r=0.414, p<0.001), eGFR (r=-0.315, p<0.01), PAI-1 (r=0.269, p<0.01), and vWF (r=0.207, p<0.01). Multiple regression analysis showed that age, cystatin C, PAI-1, and a history of CAD were independent variables of CAVI. Age-adjusted CAVI was highest in the presence of both CAD and renal impairment.
Conclusion: CAVI was closely associated with cystatin C levels. These results suggest a significant role of arterial stiffness in renal insufficiency.

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Aim: The prognostic power of metabolic syndrome (MetS) in patients with diabetes has been studied with inconsistent results depending on the definition of MetS. To clarify the best combination of MetS components to predict future cardiovascular disease (CVD) events, we estimated CVD risk in Japanese patients with type 2 diabetes according to MetS components.
Methods: Patients were categorized according to the presence three MetS components in addition to hyperglycemia. hypertension, dyslipidemia and excess waist circumference (WC) (according to either Japanese or Asian cut-off values). Hazard ratios for CVD events were compared in patients with various categories of MetS components.
Results: At least two components of MetS were required for a significantly elevated risk for CVD; however, component combinations with significantly increased risk differed depending on gender or the WC cut-off value. Any two among 1) excess WC (men ≥90 cm, women ≥80 cm); 2) hypertension (systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or use of an antihypertensive agent); and 3) dyslipidemia (triglycerides ≥150 mg/dL or HDL-cholesterol <40 mg/dL or use of drug treatment) could be used to identify significantly higher risk (approximately twice) for CVD regardless of gender.
Conclusions: The results suggest that the current MetS criteria should be modified when applied to patients with type 2 diabetes.

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Aim: Endothelin-1 (ET-1) promotes vasoconstriction and cell proliferation, and has been implicated in hypertension and coronary artery disease. Our aim was to analyse the role of the ET-1 gene (EDN1) in the risk for atherosclerosis/myocardial infarction (MI) in a population with smoking as the prevalent risk factor.
Methods: The study included 316 patients with early onset MI (<55 yeras old). All were male with at least one diseased coronary vessel. Denaturing high performance liquid chromatography (DHPLC), single-strand conformation analysis (SSCA), and direct sequencing were used to search for DNA variants in the five EDN1 exons and the promoter region. To determine the association of EDN1 polymorphisms with MI, we genotyped the patients and controls (n=350) and compared the allele and genotype frequencies between groups.
Results: We found six common nucleotide changes: -1394 (T/G) and -974 C/A (promoter), +120 ins/del A (exon 1, 5' UTR), 568 A/G (exon 3, E106E), 844 G/T (exon 5, K198N), and 1617 T/C (exon 5, 3' UTR). No rare EDN1-variants specific to the MIpatients were found. None of the EDN1 polymorphisms were significantly associated with early-onset MI in our population. The two promoter polymorphisms were in linkage disequilibrium with K198N, but no haplotype was associated with MI risk.
Conclusions: In our population, the EDN1 variation did not contribute to early-onset MI.

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Background: Increased aerobic capacity can reduce the incidence of cardiovascular disease and the mortality rate. On the other hand, a prolonged heart rate corrected-QT (QTc) interval is associated with an increased risk of arrhythmias, cardiac sudden death and coronary artery disease.
Aims: The association of the aerobic capacity and coronary risk factors with QTc interval was investigated in postmenopausal overweight women.
Subjects and Methods: The subjects included 84 postmenopausal overweight women [age: 58.7±6.4 years, body mass index (BMI): 27.9±3.3] with coronary risk factors. Electrocardiogram (ECG) was recorded with a standard resting 12-lead ECG after more than 5 minutes of rest. The QTc interval was automatically calculated according to Bazett's formula. A multistage graded submaximal exercise test was performed on an electric bicycle ergometer to determine the estimated maximal oxygen uptake (VO₂max).
Results: Single correlation analysis showed the QTc interval to be positively associated with hemoglobin A₁c (HbA₁c), fasting glucose, fasting insulin, BMI, waist circumference, serum potassium and the number of coronary risk factors, while negatively correlated with VO₂max. Stepwise multiple regression analysis demonstrated the strong association of the QTc interval with HbA₁c and VO₂max (r²=0.244, p<0.0001). In both patients with and without metabolic syndrome (n=15, n=69, respectively), the QTc interval was independently associated with the HbA₁c (r²=0.318, p<0.05, r²= 0.115, p<0.05, respectively).
Conclusions: These results suggest that decreased aerobic capacity and glucose intolerance may be independent risk factors for a prolonged QTc interval, while demonstrating no relationship with metabolic syndrome.

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Aim: We examined the hypothesis that there is a positive, independent association between polymorphisms of lamin A/C gene (LMNA) and arterial stiffness in Japanese.
Methods: The subjects were 261 men (mean age, 64.4±0.7 years) selected from inhabitants of the towns of Tanno and Sobetsu in a rural area of Japan who underwent medical check-ups. We conducted clinical examinations, including measurement of bilateral brachial-ankle pulse wave velocity (baPWV) as a marker of arterial stiffness, and genetic analysis. Subjects with atrial fibrillation, subjects with ankle-brachial index <0.9, and subjects taking any medication were excluded. We selected two single nucleotide polymorphisms (SNPs) as markers of LMNA, 1908C/T in exon 10 and -1030C/T in the promoter region, which we have recently identified. All genotypes were clearly determined by the TaqMan PCR method.
Results: Genotype frequencies of the two polymorphisms satisfied the Hardy-Weinberg equilibrium. The baPWV of -1030C/T polymorphism was significantly greater in subjects with CC genotype than in subjects with CT+TT genotype (1,652±22.1 cm/s vs. 1,552±43.0 cm/s, p=0.039); however, no significant difference was found for 1908C/T polymorphism. The baPWV was found to be significantly associated with age, body height, systolic blood pressure, and smoking habit; therefore, we next performed multiple regression analysis including these parameters, and found an independent, significant association between baPWV and -1030C/T polymorphism.
Conclusion: Promoter -1030C/T polymorphism of LMNA is a possible genetic predisposition to arterial stiffness in the Japanese population.

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Aim: A new antibody reacted with an epitope in Lp(a) that has undergone oxidation treatment, but is not present in native Lp(a), was developed. Thus, we determined serum oxidized Lp(a) concentration in healthy volunteers, and coronary artery disease (CAD), diabetes mellitus (DM), and hypertensive patients.
Methods: We measured serum levels of oxidized Lp(a), Lp(a), LDL-cholesterol and HDL-cholesterol in 122 consecutive patients who underwent routine coronary angiography and had significant coronary artery stenosis (>75%), and 164 age-matched healthy volunteers. Moreover, serum native Lp(a), oxidized Lp(a) concentration, and pulse wave velocity (PWV) were determined in 181 hypertensive patients.
Results: Oxidized Lp(a) level in CAD patients with DM was significantly higher than in healthy volunteers (p<0.01). Moreover, serum oxidized Lp(a) concentration showed a significant positive correlation with pulse wave velocity, an index of arteriosclerosis (r=0.431, p<0.01). Of importance, the deposition of oxidized Lp(a) was readily detected in calcified areas of coronary arteries in patients with myocardial infarction.
Conclusion: The present study demonstrated that oxidized Lp(a) may be a new risk factor for coronary artery disease. As the deposition of oxidized Lp(a) was detected in calcified areas of coronary arteries, oxidized Lp(a) might be implicated in endothelial dysfunction.

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Aim: Since inflammation is an important contributor to atherosclerosis, gene variants mediating inflammation are of interest. We investigated gene variants in acute phase serum amyloid-A (SAA), a sensitive indicator of inflammatory activity, and their associations with cardiovascular disease (CVD) and HDL cholesterol. Interaction of the SAA genes with genetic variants of their regulators, IL-1, IL-6 and TNF-α in influencing CVD was also explored.
Methods: SNPs characterizing common variation in the SAA1 and SAA2 genes were genotyped in European-(EA) and African-American (AA) participants (n=3969 and n=719) of the Cardiovascular Health Study. Using linear and Cox proportional hazards regression, we assessed associations of SNPs with baseline carotid artery intima-media thickness (cIMT) and risk of incident myocardial infarction, ischemic stroke, total CVD events or mortality during ˜14 years of follow-up.
Results: No associations between SAA SNPs and outcomes were observed in EA, with the exception of total CVD events; each rs4638289 minor allele was associated with an increased risk in obese individuals, HR=1.2 (95%CI: 0.981.4; p=0.086) and decreased risk among non-obese, HR=0.9 (95%CI: 0.80.99; p=0.026). In AA, we observed modest associations between SAA SNPs and cIMT, potentially modified by HDL. SAA SNPs were also associated with lower HDL in EA and AA. Suggestive gene-gene interaction findings for cIMT in AA and CVD mortality in EA were not significant in subsequent model selection tests.
Conclusion: Associations of SAA SNPs with cIMT, HDL and total CVD events were identified, unadjusted for multiple testing. These findings should be regarded as hypothesis-generating until confirmed by other studies.

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Aim: This research aims to examine the relationship of waist circumference with cardiovascular risk factors and to determine optimal cutoffs for waist circumference in the context of cardiovascular risk factors in a Japanese population.
Methods: Study subjects were 8,275 Japanese men and women aged 5074 years in Fukuoka City who participated in the baseline survey of a cohort study on lifestyle-related diseases. We defined high blood pressure, elevated non-HDL cholesterol, low HDL cholesterol, and elevated hemoglobin A1c. Odds ratios were obtained using multiple logistic regression analysis of cardiovascular risk factors in relation to waist circumference. Receiver operating characteristic curve analysis was performed to determine optimal cutoffs for waist circumference in relation to the multiplicity of cardiovascular risk factors.
Results: Waist circumference was strongly and positively associated with the prevalence odds ratios of each cardiovascular risk factor and multiplicity of these risk factors in both men and women. The optimal value of waist circumference predicting cardiovascular risk factors was 85 cm for both men and women.
Conclusion: The findings add evidence that waist circumference is an important correlate of cardiovascular factors and lend further support to the Japanese criterion for central obesity for men, but not for women.

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Aim: Recent studies have demonstrated that serum adiponectin and its receptors in adipose and muscle tissues are suppressed in diabetic or obese individuals. Patients with pheochromocytoma are frequently diabetic.
Methods: Using real-time PCR, we examined mRNA expressions of adiponectin (Adp) and adiponectin receptor 1 (AdpR1) and AdpR2 in pheochromocytoma tissues from 49 patients. We also measured levels of serum total and high molecular weight (HMW) adiponectin levels in 10 pheochromocytomas and 33 normal volunteers.
Results: In pheochromocytoma tissue, AdpR1 mRNA expression was higher in adrenaline (A)-type tumors than in noradrenaline (NA)-type tumors. AdpR1 expression was significantly higher in A-type non-diabetics than in NA-type non-diabetics (p<0.05). AdpR1 mRNA expression was significantly associated with the tumor tissue adrenaline content (p<0.005) in linear regression analysis, which suggest that adrenaline positively regulates AdpR1 mRNA expression.
Serum total and HMW Adp levels in patients with NA-type pheochromocytomas were approximately 3 times higher than those of healthy volunteers. After adrenalectomy, levels of adiponectin normalized.
Conclusion: Our results indicate that serum total and HMW Adp, and AdpR1 gene expressions in pheochromocytoma tissue, are associated with the level of catecholamine produced in the tumor. It is tempting to speculate that catecholamine induces adiponectin production and signaling.

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Aim: Alpha2-Heremans Schmid glycoprotein (AHSG), also known as fetuin-A, is secreted from the liver and inhibits tyrosine kinase activity of the insulin receptor. Hyperglycemia in type 2 diabetes is not only a secondary manifestation of insulin resistance, but could also be responsible for directly inducing insulin resistance in target tissues. In this study, we examined the effect of high glucose (HG) on AHSG gene transcription in the human hepatoma cell line HepG2.
Methods: AHSG transcriptional activity and protein expression were evaluated using reporter gene assays and Western blot analysis, respectively.
Results: D-glucose, but not L-glucose or mannitol, dose-dependently enhanced AHSG promoter activity. HG (25 mM) also increased AHSG protein expression. No protein kinase C inhibitors (bisindolylmaleimide, Ro-31-8220), an inhibitor of hexosamine biosynthesis pathway (6-diazo-5-oxo-L-norleucine), or a superoxide radical scavenger (tempol) affected HG-induced transactivation. MAPK/ERK kinase inhibitors (PD98059, U0126), but not the JNK inhibitor (SP600125) or p38 inhibitor (SB203580), significantly inhibited promoter activation by HG.
Conclusion: Our data suggest that HG enhances AHSG transcription through activation of the ERK1/2 signaling pathway. Increased AHSG expression in the liver may be a cause of glucose toxicity in the diabetic state.

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Aim: Aging and postmenopausal women are associated with increased risks of cardiovascular disease; however, epidemiological evidence concerning the relationship of aging and the menopause with vascular biological activity is limited.
Methods: We investigated the relationship of aging and the menopause with urinary excretion of cyclic guanosine 3',5' monophosphate (cGMP) in 1,541 Japanese men and women aged 40 to 79 years. The 24-hour urinary excretion of cGMP was measured with a ¹²⁵I-labeled cGMP radioimmunoassay and was adjusted for urinary creatinine excretion (nmol/mmol creatinine).
Results: Aging was positively associated with urinary excretion of cGMP for both sexes. Postmenopausal women excreted significantly less urinary cGMP than premenopausal women after adjustment for age and other cardiovascular risk factors: 48.3±0.04 nmol/mmol vs. 61.5±0.07 nmol/mmol, p=0.006.
Conclusions: Our data suggest that cGMP-related vasodilatation is impaired in postmenopausal women.

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Aim: Dietary fatty acids affect atherogenesis, which was presumed to be partly related to HDL cholesterol (HDL-C) metabolism. The major aim of the work was to analyze various ratios of n-6/n-3 PUFA diets on HDL-C metabolism in apolipoprotein E-null (apoE^-/-) mice, which have similar symptoms to human type III familial hyperlipoproteinemia.
Methods: Two-month-old male apoE^-/- mice were fed four types of n-6/n-3 PUFA diet (group 1, 1.28; group 2, 5.03; group 3, 9.98 and group 4, 68.26) and control diet, respectively, for 6 weeks. With respect to serum apolipoprotein (apo) A-I concentration, lecithin-cholesterol acyltransferase (LCAT) activity and mRNA abundance of genes involved in HDL-C metabolism in the liver were analyzed.
Results: Group 4 diet significantly increased the plasma HDL-C and apoA-I concentrations compared with other groups. LCAT activity in serum increased with decreased ratios of n-6/n-3 PUFA. As the dietary ratio of n-6/n-3 fatty acids increased, so did mRNA levels of hepatic apoA-I, scavenger receptor B class-1 (SR-B1), LCAT, ATP binding cassette transporter A1 (ABCA1), ABCG1 and liver X receptor alpha (LXRα). ApoA-II mRNA level, however, had a tendency to fall. Group 4 diet increased apoA-I and ABCA1 and decreased apoA-II transcriptional levels, whereas group 1 diet decreased mRNA levels of apoA-I, LCAT, SR-B1 and ABCG1.
Conclusion: Our data indicated that a high ratio of n-6/n-3 PUFA increased the serum HDL-C level, but did not effectively suppress atherogenesis in apoE^-/- mice. The elevated HDL-C level is possibly due to up-regulated hepatic apoA-I and ABCA1 with suppression of apoA-Ii expression.

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Aim: Our aim was to determine the roles of the ubiquitin (Ub)-proteasome system (UPS) in valvular diseases by immunohistochemically identifying Ub-positive cells in aortic and mitral valves and determining if Ub+cells were associated with the severity of valvular diseases.
Methods: We evaluated surgically removed aortic and mitral valves from 60 patients (mean age, 64.5 years) for thickening, fibrosis, foam cell infiltration, thrombus, and atheromatous plaques by using grading scores. U+cells were detected immunohistochemically.
Results: We found Ub+cells in 16 (26.7%) of the 60 patients. Eleven (28.2%) of the 39 aortic valves and 5 (23.8%) of the 21 mitral valves were Ub-positive. Ub was found with granular depositions in the cytoplasm of monocyte-derived foam cells that were CD68+. The aortic valvular thickness of the Ub+group was significantly greater than that of the Ub- group (3.9±1.6mm vs. 3.2±1.6mm, p<0.05). Foam cells and fibrosis were greater in the Ub+group (p<0.05), and calcifications were prominent in aortic valves. There was no difference in the number of apoptotic cells in Ub+ and Ub- groups. Ub+cells were present in the affected valves and ubiquitinated proteins were accumulated in macrophage-derived foam cells.
Conclusions: Ub+ foam cells are present in valves that are vulnerable to valvular disease, and UPS may contribute to the development of atherosclerosis through the inflammatory process.

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Aim: Dihomo-γ-linolenic acid (DGLA) is an n-6 polyunsaturated fatty acid that is mainly metabolized to an anti-inflammatory eicosanoid, prostaglandin (PG) E1, via the cyclooxygenase (COX) pathway. We evaluated the effect of DGLA on atherosclerosis in apoE-deficient mice and studied the mechanism of the anti-atherosclerotic effect.
Methods: ApoE-deficient mice were fed a normal diet supplemented with 0.5% DGLA or vehicle for 6 months. ApoE-deficient mice were also fed a high-cholesterol diet supplemented with 0.5% DGLA or vehicle for 1 month. To clarify the influence of a COX inhibitor, naproxen, on the anti-atherosclerotic effect of DGLA, age-matched apoE-deficient mice fed a high-cholesterol diet supplemented with 0.5% DGLA were given oral naproxen for 1 month.
Results: In normal diet-fed mice, acetylcholine-induced vascular relaxation was significantly greater in the DGLA group than in the vehicle group. NADPH oxidase subunits, p22phox and gp91phox, intercellular adhesion molecule-1, and vascular cellular adhesion molecule-1 were significantly lower in the DGLA group than in the vehicle group, and DGLA significantly prevented atherosclerosis. In high-cholesterol diet-fed mice, DGLA also significantly prevented atherosclerosis, but the anti-atherosclerotic effect was attenuated by naproxen.
Conclusion: DGLA may have an anti-atherosclerotic effect in apoE-deficient mice via PGE1 formation.

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Objective: To investigate the effect of pitavastatin on asymptomatic atherosclerosis in patients with hypercholesterolemia.
Methods: Thirty-five outpatients with hypercholesterolemia (61.5±12.8 yr) were administered 2 mg oral pitavastatin daily for 6 months. Plasma pentraxin 3 (PTX3), a novel inflammatory marker of atherosclerosis, was measured together with the serum hsCRP and carotid-artery intima-media thickness (IMT).
Results: Significant improvement of the LDL-C/HDL-C and log (TG/HDL-C) ratios began to be observed from 1 month after using pitavastatin. Significant correlation of the initial PTX3 value was observed with the initial plaque score (PS) (p=0.038, r=0.246), but not between the hsCRP and plasma PTX3 or PS. When patients were divided into 3 groups based on the initial PTX3 values, a significant decrease of the plasma PTX3 was obtained in the highest PTX3 group alone (p=0.034). The change in the plasma PTX3 value (ΔPTX3) was significantly correlated with the Δ mean IMT during the study period (p=0.008, r=0.456).
Conclusion: Pitavastatin significantly reduced the elevated plasma levels of PTX3 in patients with hypercholesterolemia by its pleiotropic effect against atherosclerotic inflammation. This study showed for the first time that the plasma PTX3 might be a useful blood parameter for direct detection of active atherosclerotic change.

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Aim: Several clinical trials have indicated that dehydroepiandrosterone (DHEA) reduces coronary events associated with atherosclerosis. The aim of this study was to examine the inhibitory effect of DHEA on atherosclerosis and the mechanisms involved.
Methods: Apolipoprotein E-knockout (apoE-KO) mice were fed an atherogenic high-cholesterol diet with or without 0.4% (w/w) DHEA for 12 weeks.
Results: Although the plasma cholesterol and triglyceride levels were not decreased by DHEA, atherosclerotic lesions in the aortic sinus showed a 45% reduction in area with DHEA treatment versus untreated mice (0.19 ± 0.01 vs. 0.10 ± 0.02 μm²; p<0.05).
Accumulation of macrophages in aortic lesions was also markedly reduced in the DHEA group, and the macrophage-positive area decreased to 0.33 ± 0.06 μm² from 0.67 ± 0.07 μm² (p<0.01). Furthermore, DHEA suppressed the expression of monocyte chemoattractant protein-1 in the vessel wall. Thus, inhibition of macrophage infiltration by DHEA reduced the formation of atherosclerotic lesions in apoE-KO mice.
Conclusions: DHEA might be an effective agent for clinical management of atherosclerosis, but a larger controlled trial is necessary for confirmation.

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Aims: Rosuvastatin is more efficacious than other statins in lowering low-density lipoprotein cholesterol (LDL-C). Studies showing higher blood levels in Asians have resulted in concerns regarding increased adverse drug reactions. This study aimed to evaluate the efficacy and safety of rosuvastatin in hypercholesterolemic Asian patients.
Methods: This retrospective observational study was conducted on statin-naive patients and statin-switch patients. Patients were treated with rosuvastatin for ≥8 weeks. Primary outcomes were changes in LDL-C levels and proportions of patients achieving their goals (primary prevention, LDL-C ≤130 mg/dL; secondary prevention, LDL-C≤100 mg/dL).
Results: Of 1007 hypercholesterolemic patients, 483 were statin-naive (LDL-C 161±40.8 mg/dL) and 524 were statin-switch patients (LDL-C 132.7±36.9 mg/dL). In statin-naive patients, rosuvastatin significantly reduced LDL-C, total cholesterol, and triglycerides by 39.9%, 28.8%, and 9.2%, respectively (p<0.001). Eighty-one percent of these patients achieved LDL-C goals. In the statin-switch cohort, LDL-C, total cholesterol, and triglycerides levels were significantly reduced by 24.5%, 16.6%, and 3.8%, respectively (p<0.001). Achievement of target LDL-C levels increased from 29% to 72.9%. There was no significant adverse drug reaction.
Conclusion: Rosuvastatin was well tolerated and effective in lowering LDL-C in hypercholesterolemic Asian patients. Patients whose LDL-C levels were suboptimal on other statins improved their levels and more achieved LDL-C goals after switching to rosuvastatin.

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Aim: Postprandial hyperlipidemia is characterized by an increase of chylomicron remnants (CM-R), and is a risk factor for atherosclerosis. Apolipoprotein (apo) B48 exists exclusively in chylomicroms and CM-R, and fasting plasma levels of apo B48 may reflect high postprandial levels of chylomicrons and/or CM-R. We hypothesized that fasting apo B48 levels may be increased in metabolic syndrome.
Methods: We investigated 1,349 inhabitants (528 men and 821 women aged 62.4±12.8 y; mean±S.D.) of two towns in rural Hokkaido, who underwent health checks in 2005.
Results: The fasting apo B48 level was significantly higher in males than females (geometric mean 1.92; 95% CI 1.802.04 μg/mL, vs. 1.69; 95% CI 1.611.76 μg/mL; p< 0.001). Ln (apo B48) showed a significant positive correlation with total cholesterol and ln (triglycerides), and a negative correlation with HDL-cholesterol. The correlation between ln (apo B48) and ln (triglycerides) was strong. Apo B48 was significantly higher in men and women with than without metabolic syndrome. Regression analysis revealed that ln (apo B48) was significantly associated with age, BMI, total cholesterol, HDL cholesterol, LDL cholesterol, and ln (triglyceride).
Conclusion: Fasting apo B48 levels are raised in individuals with metabolic syndrome.

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