Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intramitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein AI (Apo-A1). Activation of the PKA pathway by a cAMP analog, (Bu)2cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter A1 (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-A1, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease.

Epidemiological evidence suggests that the ratio HDL-cholesterol (HDL-C)/total cholesterol (TC) or apolipoprotein A1 (apo A1)/apolipoprotein B (apo B) are good indicators of coronary heart disease risk. In investigating the distribution of these ratios in the typical population served by our routine laboratory, we analysed the lipid results of 541 serum samples submitted over a 2-month period for TC, HDL-C, apo A1, and apo B. Good correlation was observed between HDL-C and apo A1 (r = 0.664), and between TC and apo B (r = 0.674). Surprisingly, the correlation between the ratios HDL-C/TC (range: 0.05-0.40) and apo A1/apo B (range: 0.27-3.71) was even higher (r = 0.822). Similar significant correlations were observed in 31 heterozygous and 20 homozygous familial hypercholesterolemic subjects, viz. the correlations between HDL-C/TC (ranges: 0.04-0.24 and 0.02-0.12, respectively) and apo A1/apo B (ranges: 0.47-1.84 and 0.15-1.12, respectively) were r = 0.951 and r = 0.972, respectively.

BACKGROUND

Microalbuminuria (MA) is associated with increased cardiovascular risk and lipid abnormalities in people with type 2 diabetes. ACE inhibitors and calcium channel blockers (CCBs) reduce MA and are neutral on total cholesterol and triglycerides. The effect of ACE inhibitors and CCBs on lipid subfractions such as Lp(a), apolipoprotein (apo) A1, apo B, and others, however, is unclear. The current study tests the hypothesis that a fixed-dose combination of an ACE inhibitor, benazepril (B) with the dihydropyridine CCB, amlodipine (A), will further reduce arterial pressure and reduce atherogenic lipid fractions compared to either agent alone.

METHODS

A multicentre, randomised, open-label, parallel group design was used to study 27 participants with type 2 diabetes. Measurements for total cholesterol, high- and low-density lipoprotein (HDL and LDL), triglycerides, apo A1, apo B, Lp(a), MA, arterial pressure and creatinine clearance were obtained at baseline and at 12-week intervals during the 36 week study.

RESULTS

Arterial pressure was significantly reduced at 36 weeks in all three groups (P = 0.0078 for A, P = 0.0039 for B, and P = 0.0313 for A+B). MA was lowered in all groups with relatively greater reductions in the B (P < 0.05) and A+B groups (P < 0.03) vs A. An increase in mean HDL-cholesterol from baseline was noted in the B and A+B groups; P < 0.05), but not in the A group. A trend was also observed between the rise in HDL-cholesterol and the reduction in MA in the B and A+B groups. Additionally, only the B group exhibited a decrease in the median value of Lp(a) (P < 0.05).

CONCLUSIONS

These data support the concept that ACE inhibition with B reduces the atherogenic profile by decreasing Lp(a) and increasing HDL-cholesterol, the latter being correlated with reductions in MA. While A+B exhibited similar trends in lipid subfractions and MA as B, this group had the greatest reduction in systolic blood pressure of the three groups. Thus, use of A+B offers the benefits of a decreased atherogenic profile with a higher probably of achieving goal blood pressure as recommended by national guidelines.

Coronary artery disease (CAD) is one of the leading causes of mortality in developed countries. Adenosine triphosphate (ATP)-binding cassette A1 (ABCA1) belongs to the superfamily of membrane proteins that function as a key factor in the regulation of plasma high-density lipoprotein cholesterol (HDL-C) and the metabolism of apolipoprotein A-I (Apo AI). The role of this gene in CAD remains controversial. The aim of this study was to investigate the frequency of single-nucleotide polymorphism (SNP) rs2230806 in the ABCA1 gene of 120 CAD patients and 100 age-matched, healthy controls using restriction fragment length polymorphism and direct sequencing. Total serum cholesterol, HDL-C and serum triglyceride levels were also assayed. Low-density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald formula. When compared, the G allele occurred significantly more frequently in CAD patients compared to the control subjects. The odds ratio (OR) for CAD conferred by carrying the ABCA1 G allele was 2.362 [95% confidence interval (CI) 0.9055-6.161] (P<0.08). The K variant of SNP rs2230806 in the G allele was associated with a decrease in HDL-C levels, but an increased frequency of CAD. In conclusion, the results showed that SNP rs2230806 in the ABCA1 gene is significantly associated with the incidence of CAD. Homozygosity for the G allelic variant in CAD patients may be associated with an increased risk of CAD/MI.

BACKGROUND

Current diagnostic methods of renal allograft rejection are neither sensitive nor specific. Needle biopsies are invasive and associated with patient morbidity. Thus, it is desirable to develop noninvasive tests to predict and diagnose rejection.

METHODS

Using a case-control approach, surface-enhanced laser desorption/ionization time-of-flight mass spectrometry was used to identify plasma proteins associated with renal allograft rejection. From each rejection patient (n=16), two plasma samples (one near the biopsy date and the other at a time postbiopsy) were compared. Biopsy-confirmed nonrejection patients (n=48) were further analyzed as controls. Antibody-based quantitative enzyme-linked immunosorbent assay was performed to validate candidate biomarker apolipoprotein A1 (Apo A1) in a subset of the original and a second cohort of biopsy-confirmed rejection (n=40) and nonrejection (n=70) patients.

RESULTS

Twenty-two proteins/peptides showed significant differences between rejection and postrejection samples. Peptides 5191 Da and 4467 Da detected rejection with 100% sensitivity and 94% specificity. The 4467 Da peptide was identified as the C-terminal fragment of α-1 antichymotrypsin and a 28 kDa protein was determined as Apo A1. Both protein levels were significantly lower at rejection compared with postrejection. Protein levels of nonrejection patients were similar to the postrejection samples. Apo A1 enzyme-linked immunosorbent assay results showed significantly lower Apo A1 levels (P=0.001 for the original and P=4.14E-11 for the second cohort) at the time of rejection compared with nonrejection which coincides with the SELDI findings.

CONCLUSIONS

Together α-1 antichymotrypsin, Apo A1, and the unidentified 5191 Da peptide provide a plasma molecular profile, and this is associated with acute cellular renal allograft rejection.

OBJECTIVE

The aim of the present study was to assess the association between the 2037T/C and 2237G/A polymorphisms in the EL gene and the risk of CAD and lipid levels in a Chinese population.

METHODS

A case-control study including 706 patients with CAD and 315 controls was performed. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to identify the genotypes.

RESULTS

The EL 2037 T/C polymorphism was associated with CAD risk and HDL-C levels. No significant differences were found between the EL 2237 G/A genotypes and CAD risk and lipid levels in the whole population. However, carriers of the 2237 A allele had higher Apo A1 levels than those with the 2237 GG genotype and in the CAD subgroup (P = 0.044). The CAD cases have a significantly lower frequency of the C-G haplotypes than the controls, and the T-A haplotype was significantly more common in the CAD patients than in the controls.

CONCLUSIONS

Our study concluded that the EL 2037 T/C polymorphism was associated with CAD risk and HDL-C levels, and that the C allele might be a protective factor against CAD in the Chinese Han population. In addition, the EL 2237 A allele might be associated with an increased Apo A1 level in CAD subjects.

Cholesterol homeostasis is essential in normal physiology of all cells. One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues. One of its main functions is the efflux of intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (Apo A-I), forming nascent high-density lipoprotein-cholesterol (HDL-C) particles, the first step of reverse cholesterol transport (RCT). In addition, ABCA1 regulates cholesterol and phospholipid content in the plasma membrane affecting lipid rafts, microparticle (MP) formation and cell signaling. Thus, it is not surprising that impaired ABCA1 function and altered cholesterol homeostasis may affect many different organs and is involved in the pathophysiology of a broad array of diseases. This review describes evidence obtained from animal models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related macular degeneration (AMD), glaucoma, viral infections and in cancer progression.

Keywords: ATP-binding cassette transporter A1 (ABCA1); HDL-C; cholesterol homeostasis; dyslipidemia; microparticles; reverse cholesterol transport; type 2 diabetes.

BACKGROUND

While elevated plasma high-density lipoprotein (HDL) levels has been associated to a reduction in cardiovascular risk, dietary fish oils rich in omega-3 polyunsaturated fatty acids (PUFAs) may protect against this disease. The protective effect of HDL is associated to its participation in the reverse cholesterol transport pathway. On the other hand, omega-3 PUFAs decrease plasma HDL levels compared to other fatty acids, which may suggest an effect on reverse cholesterol transport.

OBJECTIVE

In this work, the effect of dietary fish oil on the fatty acid composition of hepatic membranes, plasma lipoprotein cholesterol profile, biliary lipids, and the expression of proteins involved in reverse cholesterol transport, was compared to other dietary oils having a different degree of fatty acid unsaturation.

METHODS

Male rats were fed a semi synthetic diet containing fish oil (omega-3), sunflower oil (omega-6), olive oil (omega-9) or coconut oil (saturated). Hepatic membrane fatty acid composition, plasma cholesterol levels, lipoprotein cholesterol profile, biliary lipids, hepatic mRNA levels for lecithin cholesterol acyltransferase, hepatic lipase, apo E, and apo A-I, and hepatic protein levels of the scavenger receptor class B type I, caveolin-1, and the ATP binding cassette transporter A1 were analyzed. Plasma apo A-I and apo E protein levels were also evaluated.

RESULTS

Compared to the other diets, omega-3 PUFAs significantly changed omega-3/omega-6 fatty acid ratio of hepatic membranes, caused a reduction of plasma total and HDL cholesterol, and selectively increased biliary cholesterol secretion. No modification in the expression levels of lecithin cholesterol acyltransferase, hepatic lipase, apo A-I and apo E mRNA was observed. Hepatic scavenger receptor class B type I, caveolin-1, and the ATP binding cassette transporter A1 protein levels were also not affected. Plasma apo A-I, but not apo E, was reduced.

CONCLUSIONS

These results show that dietary omega-3 PUFAs reduce plasma HDL cholesterol and increase biliary cholesterol without concomitant modifications in the expression of key genes and proteins involved in reverse cholesterol transport. These findings suggest that functional changes in the activity of these proteins as consequence of the incorporation of omega-3 PUFAs into hepatic membranes and plasma lipoproteins may underlie the effect of fish oil feeding on plasma and hepatic cholesterol metabolism in the rat.

OBJECTIVE

Due to the complex relationship between kisspeptin and the hypothalamic-pituitary-gonadal axis, the study was planned to measure the kisspeptin levels in polycystic ovary syndrome (PCOS) and to analyze the correlations between kisspeptin and PCOS-related reproductive, metabolic changes.

METHODS

The study was designed as a prospective study in Dokuz Eylul University between December 2011 and September 2013. A total of 285 PCOS cases and 162 controls were recruited. After the antropometric measeruments and physcial examination, blood samples were taken for biochemical analysis.

RESULTS

PCOS group's mean BMI was 24.32 ± 3.40 and for the control group, BMI value was 23.44 kg/m2 ± 4.08 (p = 0.351). PCOS patients' FSH level was 5.10 ± 2.01 mIU/L, LH value was 7.75 ± 4.31 mIU/mL, LH/FSH ratio was 1.70 ± 1.28, DHEAS value was 221.84 ± 105.02 mg/dl, total testosterone value was 50.51 ± 27.93 ng/ml, free testosterone value was 2.52 ± 1.05 pg/ml, SHBG was 63.74 ± 45.62 nmol/L, LDL was 102.56 ± 23.45 mg/dL, HDL value was 51.36 ± 12.15 mg/dL, total cholesterol value was 214.85 ± 39.27 mg/dL, triglyceride value was 112.95 ± 46.88 mg/dL, Apo A1 value was 171.30 ± 35.35 mg/dL, Apo B value was 71.08 ± 19.07 mg/dL, Apo B/A1 ratio was 0.42 ± 0.14, free androgen index was 13.77 ± 14.15, fasting glucose value was 80.68 ± 13.80 mg/dL, fasting insulin levels was 14.13 ± 9.11 μiU/mL, HOMA-IR index was 2.76 ± 2.34, AMH value was 5.93 ± 3:33 in ng/ml, and found to be significantly higher (p < 0.001). Leptin value was 9.71 ± 5.54 pg/ml and kisspeptin value was 1.92 ± 1.29 ng/ml, respectively. Kisspeptin and leptin levels showed no statistically significant difference with control group and PCOS group. In all PCOS patients, kisspeptin showed positive correlations between LH and leptin levels.

CONCLUSIONS

In this study, kisspeptin had a positive correlation with LH and leptin levels in PCOS. In fact, the serum levels of kisspeptin and leptin does not differ statistically between PCOS and healthy women. There are limited data in the literature with regard to changes in kisspeptin levels and its relation with metabolic and hormonal disturbances.

Dietary fat may be associated with coronary heart disease (CHD). Studies suggest that restricting fat intake may compromise endurance performance and that increasing fat intake may improve endurance performance. We studied the effects of varying dietary fat intake on CHD risk factors in runners. Twelve male and 13 female runners increased fat from 16% to 30% of daily calories (4 wk each). Of this group, six males and six females increased fat to 42% of daily calories (4 wk). Physiological and lipoprotein risk factors were measured after each diet. Results were analyzed by repeated measures ANOVA. Increasing dietary fat from 16% to 42% of daily calories did not change adiposity, weight, heart rate, blood pressure, serum triglycerides, total cholesterol, LDL cholesterol. Apolipoprotein B, or the Apo A1/Apo B ratio. Compared with those eating higher fat, subjects eating 16% fat had lower HDL cholesterol (50 +/- 3 vs 62 +/- 3 mg.dl-1, P < 0.0001) and Apolipoprotein A1 (111 +/- 6 v. 134 +/- 6 mg/dl, P < 0.0005) and a higher TC/HDL-C ratio (4.05 +/- 0.27 vs 3.42 +/- 0.24, P < 0.0005). Runners who increased fat intake to 42% further raised HDL cholesterol (64 +/- 6 to 69 +/- 5 mg.dl-1, P < 0.04) without adversely affecting other lipoproteins. In conclusion, a 42% fat diet maintained favorable CHD risk factors in female and male runners whereas a 16% fat diet lowered Apo A1 and HDL-C and raised the TC/HDL-C ratio.

Coronary artery disease (CAD) is one of the largest causes of death worldwide yet the traditional risk factors, although useful in identifying people at high risk, lack the desired predictive accuracy. Techniques like quantitative plasma proteomics holds immense potential to identify newer markers and this study (conducted in three phases) was aimed to identify differentially expressed proteins in stable CAD patients. In the first (discovery) phase, plasma from CAD cases (angiographically proven) and controls were subjected to iTRAQ based proteomic analysis. Proteins found to be differentially expressed were then validated in the second and third (verification and validation) phases in larger number of (n = 546) samples. After multivariate logistic regression adjusting for confounding factors (age, diet, etc.), four proteins involved in the reverse cholesterol pathway (Apo A1, ApoA4, Apo C1 and albumin) along with diabetes and hypertension were found to be significantly associated with CAD and could account for approximately 88% of the cases as revealed by ROC analysis. The maximum odds ratio was found to be 6.70 for albumin (p < 0.0001), followed by Apo AI (5.07, p < 0.0001), Apo CI (4.03, p = 0.001), and Apo AIV (2.63, p = 0.003). Down-regulation of apolipoproteins and albumin implicates the impairment of reverse cholesterol pathway in CAD.

OBJECTIVE

Angiogenesis performs a critical role in the development of cancer. Angiogenesis research is a cutting-edge field in cancer research. Proteomics is a powerful tool in identifying multiple proteins that are altered following a neuropharacological intervention in a disease of the central nervous system. Diagnostic oncoproteomics is the application of proteomic techniques for the diagnosis of malignancies.

METHODS

We extracted proteins of tumor and normal brain tissues and then evaluated the protein purity by Bradford test and spectrophotometery method. In this study, we separated proteins by two-dimensional (2D) gel electrophoresis method and the spots were then analyzed and compared using statistical data and specific software, after providing three-dimensional images of spots alteration. Spots were identified by pH isoelectric, molecular weights, and data banks.

RESULTS

Simple statistical test were used to establish a putative hierarchy in which the change in protein level were ranked according a cutoff point with P < 0.05. Apolipoprotein A1 (apo A1) protein and albumin were consistently upregulated in astrocytoma brain tumors.

CONCLUSIONS

The vascular microenvironment of glioma play a major role in determining the pathophysiological character is tics of the tumor. apo A1 and albumin are very significant due to their functional consequences in glioma tumor growth, migration and angiogenesis.

OBJECTIVE

Whether menopausal stage is associated with abnormalities in serum lipid and lipoprotein profiles remains unclear; studies have been conducted mostly in Western populations. This study aimed to examine the prevalence of lipid and lipoprotein abnormalities by recently updated menopausal stages in middle-aged women.

METHODS

This study was cross-sectional analysis of 1553 women aged 44-56 years, who underwent a comprehensive health screening examination in the Kangbuk Samsung Hospital Total Healthcare Centers, Korea, during 2012-2013. Lipid and lipoprotein profiles including total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), lipoprotein (a) (Lp(a)), apolipoprotein A1 (Apo A1), apolipoprotein B (Apo B) were assessed. Prevalence ratios and 95% confidence intervals for lipid and lipoprotein abnormalities were estimated by menopausal stages as defined by the 2011 Stages of Reproductive Aging Workshop+10 criteria.

RESULTS

Increased prevalence of lipid and lipoprotein abnormalities were observed across menopausal stages. The increased prevalence of high non-HDL-C was associated with the late menopausal transition and post-menopausal stages and was more pronounced in women with body mass index (BMI) <23 kg/m(2) than in those with BMI ≥23 kg/m(2) (P for interaction=0.006). Similarly, there was an interaction between BMI and menopausal stages in relation to high Apo B (P for interaction=0.05) and high Apo B/Apo A1 ratio (P for interaction=0.06).

CONCLUSIONS

Our findings extend previous results and suggest that the increased prevalence of lipid and lipoprotein abnormalities was associated not only with the post-menopausal stage but also late menopausal transition period.

Therapeutic interventions that increase plasma high density lipoprotein (HDL) and apolipoprotein (apo) A-I levels have been reported to reduce plasma glucose levels and attenuate insulin resistance. The present study asks if this is a direct effect of increased glucose uptake by skeletal muscle. Incubation of primary human skeletal muscle cells (HSKMCs) with apoA-I increased insulin-dependent and insulin-independent glucose uptake in a time- and concentration-dependent manner. The increased glucose uptake was accompanied by enhanced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), the serine/threonine kinase Akt and Akt substrate of 160 kDa (AS160). Cell surface levels of the glucose transporter type 4, GLUT4, were also increased. The apoA-I-mediated increase in glucose uptake by HSKMCs was dependent on phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt, the ATP binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-B1). Taken together, these results establish that apoA-I increases glucose disposal in skeletal muscle by activating the IR/IRS-1/PI3K/Akt/AS160 signal transduction pathway. The findings suggest that therapeutic agents that increase apoA-I levels may improve glycemic control in people with type 2 diabetes.

Long non-coding RNAs (lncRNAs) are important biological mediators that regulate numerous cellular processes. New experimental evidence suggests that lncRNAs play essential roles in liver development, normal liver physiology, fibrosis, and malignancy, including hepatocellular carcinoma and cholangiocarcinoma. In this review, we summarise our current understanding of the function of lncRNAs in the liver in both health and disease, as well as discuss approaches that could be used to target these non-coding transcripts for therapeutic purposes.

Keywords: ABCA1, ATP-binding cassette transporter A1; ACTA2/ɑ-SMA, α-smooth muscle actin; APO, apolipoprotein; ASO, antisense oligonucleotides; BDL, bile duct ligation; CCA, cholangiocarcinoma; CCl4, carbon tetrachloride; COL1A1, collagen type I α 1; CYP, cytochrome P450; Cholangiocarcinoma; DANCR, differentiation antagonising non-protein coding RNA; DE, definitive endoderm; DEANR1, definitive endoderm-associated lncRNA1; DIGIT, divergent to goosecoid, induced by TGF-β family signalling; DILC, downregulated in liver cancer stem cells; EST, expression sequence tag; EpCAM, epithelial cell adhesion molecule; FBP1, fructose-bisphosphatase 1; FENDRR, foetal-lethal non-coding developmental regulatory RNA; FXR, farnesoid X receptor; GAS5, growth arrest-specific transcript 5; H3K18ac, histone 3 lysine 18 acetylation; H3K36me3, histone 3 lysine 36 trimethylation; H3K4me3, histone 3 lysine 4 trimethylation; HCC, hepatocellular carcinoma; HEIH, high expression In HCC; HNRNPA1, heterogenous nuclear protein ribonucleoprotein A1; HOTAIR, HOX transcript antisense RNA; HOTTIP, HOXA transcript at the distal tip; HSC, hepatic stellate cells; HULC, highly upregulated in liver cancer; Hepatocellular carcinoma; HuR, human antigen R; LCSC, liver cancer stem cell; LSD1, lysine-specific demethylase 1; LXR, liver X receptors; LeXis, liver-expressed LXR-induced sequence; Liver cancer; Liver fibrosis; Liver metabolism; Liver-specific lncRNAs; LncLSTR, lncRNA liver-specific triglyceride regulator; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; MEG3, maternally expressed gene 3; NAT, natural antisense transcript; NEAT1, nuclear enriched abundant transcript 1; ORF, open reading frame; PKM2, pyruvate kinase muscle isozyme M2; PPAR-α, peroxisome proliferator-activated receptor-α; PRC, polycomb repressive complex; RACE, rapid amplification of cDNA ends; RNA Pol, RNA polymerase; S6K1, S6 kinase 1; SHP, small heterodimer partner; SREBPs, steroid response binding proteins; SREs, sterol response elements; TGF-β, transforming growth factor-β; TTR, transthyretin; XIST, X-inactive specific transcript; ZEB1, zinc finger E-box-binding homeobox 1; ceRNA, competing endogenous RNA; eRNA, enhancer RNAs; lincRNA, long intervening non-coding RNA; lncRNA; lncRNA, long non-coding RNA; mTOR, mammalian target of rapamycin; siRNA, small interfering RNA.

Atherosclerotic vessels were analysed histochemically for distribution, quantity, and composition of apolipoprotein (Apo) types in the vascular wall. The specimens comprised all stages of atherosclerosis, from very discrete intimal changes to complicated lesions. The vessel specimens were marked with antibodies against human Apo A1, A2, and B. Apo A1 can be demonstrated in even the earliest stage of atherosclerosis, and increases with the progression of the disease. In the initial stage, Apo A1 is found first in lumen-adjacent layers of the intima, and is evident in deeper layers of the wall as the disease progresses. Arteries of muscular type show accumulation of Apo in an earlier stage (or in greater quantity at the same stage) than arteries of elastic type. At all stages, the amount of Apo A1 always exceeds that of A2 and B. In the intima, Apo B is higher than Apo A2, the media contains hardly any Apo B, and the adventitia has less B than A2. Within the intimal layer, Apo A1 and A2 are found in an intracellular (mainly in foam cells) or in an extracellular location, according to the stage of atherosclerosis. Apo B is almost exclusively extracellular; only cases of advanced atherosclerosis show some intracellular localization (mostly in foam cells), visualized as electron dense lamellar organelles, probably of lysosomal origin. In the media, Apo A1 and A2 are accumulated in intracellular deposits, whereas the extracellular storage of Apo A1, A2 and B is observed only in cases with the most severe damage. Our investigations suggest that the accumulation of apolipoproteins in the vascular wall is affected not only by insudation from the plasma, but also by neosynthesis and/or metabolism by locally derived cells or cells immigrating in the process of atherosclerosis. The presence of Apo A1 and A2 in the vessel wall is now documented, and their role at this site apparently differs from that in the plasma.

OBJECTIVE

Coronary artery disease (CAD) is a leading cause of death globally with increasing burden in South Asians in the US. Specific genetic variants that influence CAD have not been fully assessed in South Asian Immigrants. The goal is to identify Apo lipoprotein A1 (APOA1) gene polymorphisms and their association with CAD risk factors, metabolic syndrome and dysfunctional HDL (Dys-HDL).

METHODS

A community-based study on South Asians aged 35--65 years without CAD was conducted. APOA1 gene sequencing was performed and genotypes compared with cardiovascular findings.

RESULTS

The prevalence of metabolic syndrome and dysfunctional-HDL was 29.7% and 26%, respectively. Six novel APOA1 gene single nucleotide peptides ({SNPs}) were analyzed. Three of the six SNPs (G2, G3, and G5) were found to be associated with metabolic syndrome; G2 (T655C) (p=0.044), G3 (T756C) (p=0.037) and G5 (T1001C) (p=0.037). APOA1 gene SNP G1 (T319C) was highly correlated with low HDL levels (p=0.001). In our study, both associations of APOA1 SNPs with metabolic syndrome and low HDL remained after age-adjustment.

CONCLUSIONS

Discovery of novel gene polymorphisms will help to understand further the causes of excess CAD risk in South Asians so that preventative strategies targeted to high-risk group can be developed.

The aim of this study was to evaluate the prevalence of arterial hypertension and other risk factors in patients suffering from peripheral arterial disease (PAD) in two clinical samples (1.: 102 patients with PAD 69 M, 33 F, studied in our angiology laboratory, matched for sex and age with 102 healthy volunteers; 2.: 184 hospitalized patients, 80 M, 104 F, mean age 57.2 +/- 10.8, with PAD) and in two epidemiological cohorts (1.: Trabia Study, 835 subjects; 2.: Casteldaccia Study, 723 subjects). All patients were subjected to a full clinical and laboratory examination, including the determination of the ankle/arm pressure ratio (Winsor index, positive for PAD when lower than 0.95). In the first clinical study we observed a significantly (p < 0.01) greater prevalence of arterial hypertension (51.9 vs 9.8%), hypercholesterolemia (48.2 vs 21.6%), hypertriglyceridemia (53.7 vs 26.1%), smoking habit (64.3 vs 44.2%), and hyperglycemia (26 vs 7,9%) in PAD patients than in controls. In the second clinical study considering separately the patients under and over 65 years, all risk factors resulted to be more prevalent in younger people than in the aged, except for diabetes and hypertension. In our epidemiological experience, the prevalence of PAD increases with aging, above all in males. In the Trabia Study the risk factors, more associated with PAD, were hypercholesterolemia, smoking and obesity (41.18%) in males and hypertension and hypercholesterolemia (33.3%) and obesity (25%) in females. In the Casteldaccia Study the most important risk factors were smoking (64.28%), hypercholesterolemia (42.86%) and hypertriglyceridemia (35.71%) in males, and obesity (60%), hypercholesterolemia (30%) and diabetes (20%) in females. Cholesterol levels and smoking were significantly higher in PAD patients than in the general population, whereas hypertriglyceridemia and glycemia were not. Arterial hypertension was significantly associated with PAD in the Trabia but not in the Casteldaccia Study. Obesity was significantly associated to PAD in females in both studies. In the Casteldaccia Study, lower HDL-cholesterol levels were observed in PAD patients, above all in males, whereas significantly greater Apo-B values and lower Apo-A1 levels (in males) were shown. The different levels of associated risk factors and their prevalence in PAD patients confirm the multifactorial pathogenesis of atherosclerosis. The exact role of each risk factor in the genesis of PAD is difficult to be evaluated due to the complex biological and statistical interrelationships among different risk factors. However, the management of associated risk factors may favourably influence the risk profile in each patient suffering from PAD.

Insulin resistance, with adipose tissue dysfunction, is one of the hallmarks of metabolic syndrome. We have reported a metabolic syndrome-like phenotype in heme oxygenase (HO)-2 knockout mice, which presented with concurrent HO-1 deficiency and were amenable to rescue by an EET analog. Apo A-I mimetic peptides, such as L-4F, have been shown to induce HO-1 expression and decrease oxidative stress and adiposity. In this study we aimed to characterize alleviatory effects of HO-1 induction (if any) on metabolic imbalance observed in HO-2 KO mice. In this regard, HO-2((-/-)) mice were injected with 2 mg/kg/day L-4F, or vehicle, i.p., for 6 weeks. As before, compared to WT animals, the HO-2 null mice were obese, displayed insulin resistance, and had elevated blood pressure. These changes were accompanied by enhanced tissue (hepatic) oxidative stress along with attenuation of HO-1 expression and activity and reduced adiponectin, pAMPK, and LKB1 expression. Treatment with L-4F restored HO-1 expression and activity and increased adiponectin, LKB1, and pAMPK in the HO-2((-/-)) mice. These alterations resulted in a decrease in blood pressure, insulin resistance, blood glucose, and adiposity. Taken together, our results show that a deficient HO-1 response, in a state with reduced HO-2 basal levels, is accompanied by disruption of metabolic homeostasis which is successfully restored by an HO-1 inducer.

Multiple studies have demonstrated that elevated serum lipoprotein (a) [Lp(a)] levels are independent predictors for coronary artery disease (CAD) in subjects without diabetes mellitus (DM). However, their contribution in patients with DM is controversial and still requires clarification. We determined serum Lp(a) levels in 355 consecutive Caucasian patients (271 men and 84 women) with angiographically documented CAD, and in 100 control subjects (58 men and 42 women) who were clinically free of cardiovascular disease. In addition, the association of serum Lp(a) levels with type-2 DM in patients with CAD was investigated after reassigning patients according to the diagnosis of type-2 DM (61 men and 40 women with type-2 DM and 210 men and 44 women without). No gender differences in Lp(a) levels were observed between men and women (patients and control subjects). Patients with CAD had higher Lp(a) levels than the control subjects (33 (14-74) vs. 13 (9-29) mg/dl, P<0.001). Elevated Lp(a) levels (defined as >90th percentile of controls) were significantly more prevalent in men and women with CAD (35% and 28%, respectively) than in control subjects (13% and 10%, respectively). Serum Lp(a) levels correlated with LDL cholesterol (r=0.22, P<0.001) and apo B levels (r=0.18, P<0.03) in patients and control subjects. Stepwise discriminant analysis revealed that Lp(a) was an independent risk factor for the presence of CAD, independent of smoking, hypertension, type-2 DM, LDL and HDL cholesterol or apo A1 and B levels. When patients were studied according to the spread of CAD (evaluated as the number of narrowed vessels), no differences in serum Lp(a) levels were observed, nor was there a higher prevalence of elevated Lp(a) levels. Finally, when patients were re-assigned according to the diagnosis of type-2 DM, no effect of apo B and LDL-C levels on Lp(a) was found (r=0.06, P=n.s. and 40.14, P=n.s., respectively) and serum Lp(a) levels neither associated nor contributed to the extent of CAD. Our results showed that serum Lp(a) levels are increased in patients with angiographically documented CAD, but there were no significant differences between diabetic and non-diabetic patients, which indicates that elevated Lp(a) levels are specifically associated with CAD but not with type-2 DM.

This study was undertaken in order to evaluate the effect of an oral contraceptive containing 35 micrograms of ethinyl estradiol and 2 mg of cyproterone acetate (Diane-35) on carbohydrate and lipid metabolism in patients with polycystic ovary syndrome (PCOS). Twenty three patients with PCOS were treated with Diane-35 for between 9 and 18 cycles without interruption (a total of 318 treated cycles). Metabolic evaluations, which included measurements of fasting blood glucose, insulin, C-peptide, total cholesterol, triglyceride, total lipids, HDL-cholesterol, LDL-cholesterol and apolipoproteins (Apo A1, Apo A2 and Apo B), were performed before treatment and every 3rd cycle during the treatment period. In the case of 5 women an oral glucose tolerance test (oGTT) was performed before and after the 12th cycle of Diane-35 treatment, with blood samples taken for glucose, insulin and C-peptide measurements. Total cholesterol showed a significant increase after the 6th cycle (p less than 0.001) and reached the mean maximal value after the 9th cycle. A similar increasing trend was observed with LDL-cholesterol, which also reached the maximal mean level after the 9th cycle of treatment (p less than 0.05). There were no significant changes in HDL-cholesterol levels. Significant increases in serum triglyceride (p less than 0.01) and total lipids (p less than 0.001) were observed after the 3rd cycle. Apo A2 concentrations increased significantly after the 6th cycle (p less than 0.001) and showed an increasing trend thereafter. A significant increase was also observed in Apo B concentrations after the 6th cycle but these decreased after the 12th cycle. In spite of these observed increases in serum lipids and lipoproteins, the mean levels remained within the normal range throughout the treatment period. Fasting serum glucose, insulin and C-peptide concentrations did not show any significant changes during the study. Higher insulin and C-peptide responses during the oGTT were observed after the 12th cycle but the differences in the areas under the curve before and after treatment were not significant. A deterioration of blood glucose was observed after treatment with Diane-35, a significant difference in mean values being noted 150 minutes after the glucose overload (p less than 0.005). However, the areas under the curve in blood glucose response before (34.92 +/- 4.12) and after (43.45 +/- 3.61) treatment were not significantly different.(ABSTRACT TRUNCATED AT 400 WORDS)

We describe three patients with Anderson's disease who are members of one family; the father and mother are close relatives and three of seven children show symptoms of the disease. All patients suffered from diarrhea, failure to thrive, and recurrent infections during infancy. Although these symptoms disappeared later in life, biochemical disorders (such as low plasma levels of apolipoproteins A1 and B and cholesterol, resulting in avitaminosis E, plus failure to secrete chylomicrons after a fat meal) persisted. Electron microscopy of enterocytes of one of the patients showed accumulation of lipid vacuoles with no significant aberration of the Golgi apparatus itself. It is possible, therefore, that the disease reflects a defect in chylomicron assembly. We found that low levels of apolipoprotein (apo) B48 were present in the patients' plasma. This suggests that the processing of the B100 message resulting in apo B48 functions normally. The possibility that a mutation in the apo B gene results in an abnormal apo B48 protein is very unlikely since a variable number tandem repeat (VNTR) polymorphism probe mapped to chromosome 2 failed to show correspondence of the parent alleles with the disease. These observations confirm the suggestion that Anderson's disease is not linked to the apo B locus.

The clinical trials described in this article were presented at the Late Breaking Trials and the Clinical Science: Clinical Reports sessions of the American Heart Association Congress held in November 2010 in Chicago. The sessions and topics chosen for this article reflect the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses may be done, which could alter the final publication of the results of these studies. PROTECT (ProBNP Outpatient Tailored Chronic Heart Failure Therapy) was designed to test the hypothesis that adjustment of intensity of chronic heart failure (HF) therapy on the basis of NT-proBNP plasma level monitoring would improve outcomes. The results provided some support of this concept, but needs further evaluation in larger, blinded trials. REVEAL (Reduction of Infarct Expansion and Ventricular Remodeling with erythropoietin after large myocardial infarctions) evaluated in the clinical setting of ischemia-reperfusion following STEMI that erythropoietin could salvage ischemic myocardium. The results did not show a reduction in infarct size, but, in contrast, an increase in adverse event rates in the erythropoietin group. GRAVITAS (Gauging Responsiveness with a VerifyNow assay-Impact on Thrombosis and Safety trial) investigated the effect of a standard vs. high maintenance clopidogrel dose in patients with stable myocardial ischemia or NSTEMI and drug-eluting stent insertion. Patients with high PRU values as determined by VerfyNow assay were randomized to 75 mg or 150 mg clopidogrel daily. The study did not show a significant difference in primary event rate between both groups. The Cholesterol Treatment Trialists' Collaboration Studies group evaluated the concept proposed in the JUPITER study that HDL levels on statin treatment may not provide useful prognostic information. The CTTC in a large sample size of statin-treated patients observed, on the contrary, a significantly increased risk of CV events, even in patients with low LDL cholesterol levels. DEFINE (Determining the Efficacy and Tolerability of CETP inhibition with Anacetrapib) evaluated possible safety aspects with the CETP inhibitor anacetrapib (increase in blood pressure). The study did not show adverse safety aspects, but significantly reduced LDL cholesterol and increased HDL cholesterol levels. ASSERT, a phase 2 dose-ranging study, investigated whether RVX-208 would increase Apo-A1 production. Apo-A1 may induce cholesterol efflux from macrophages and facilitate atherosclerosis regression. The study did not meet its primary endpoint, but significant prominent effects on lipids were found. ASCEND-HF was a large trial of nesiritide in >7000 patients with acute heart failure. The study did not show convincing symptom benefit, but on the other hand did not show harmful effects of nesiritide. EMPHASIS-HF evaluated the long term effects of eplerenone in patients with mild (NYHA class II) heart failure and systolic dysfunction. The study was prematurely ended because of highly significant beneficial effects. CUPID (Calcium Up-regulation by Percutaneous administration of gene therapy In cardiac Disease) is the first human study with gene transfer of SERCA2a (AVV1/SERCA2a: Mydicar). In a small placebo-controlled dose-ranging study in advanced heart failure patients a multiple endpoint analysis provided positive effects of the highest dose on symptomatic, functional and structural efficacy endpoints without adverse effects.