Relationship between Discordance of Low-Density Lipoprotein and Non-High-Density Lipoprotein Cholesterol and Risk Stratification in Acute Myocardial Infarction

Abstract Background: Sizeable proportion of patients have discordant low-density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (NHDL-C). It has been shown that discordance of LDL-C and NHDL-C either underestimates or overestimates coronary risk. Objectıve: We assessed whether this discordance has an impact on GRACE and TIMI risk scores in patients with acute myocardial infarction (AMI). Methods: We retrospectively evaluated the data of 198 consecutive patients with AMI. Fasting serum lipid profiles were recorded, GRACE and TIMI scores were calculated. Patients were divided into 3 groups according to LDL-C and NHDL-C percentiles: Discordant group: LDL-C<NHDL-C (n=38), concordant group: LDL-C=NHDL-C (n=112) and discordant group LDL-C>NHDL-C (n=48). GRACE and TIMI scores, mortality and cardiovascular events (heart failure, non-fatal myocardial infarction and angina) at sixth month were compared between these three groups. Differences between these groups were analyzed with One-way ANOVA or Kruskal-Wallis rank test, and with chi-square for percentages. Also, post hoc LSD or Conover-Iman's non-parametric multiple comparison test were used. A p value <0.05 was accepted as statistically significant. Results: TIMI risk score didn't differ between discordant or concordant groups. Mean GRACE (death) and GRACE (death and MI) scores were higher in group with LDL-C<NHDL-C than with LDL-C=NHDL-C and LDL-C>NHDL-C (p=0.029 and 0.008, respectively). Cardiovascular events and mortality at sixth month were not different among groups (p=0.473 and p=0.176, respectively). Conclusion: GRACE score was higher in discordant group with LDL-C<NHDL-C, but there is no difference regarding TIMI scores between discordant and concordant groups in AMI patients.

Amyloid-beta transporter expression at the choroid plexus in normal aging: the possibility of reduced resistance to oxidative stress insults / 生理学报

Accumulation of amyloid-beta peptides (Aβ) results in amyloid burden in normal aging brain. Clearance of this peptide from the brain occurs via active transport at the interfaces separating the central nervous system (CNS) from the peripheral circulation. The present study was to investigate the change of Aβ transporters expression at the choroid plexus (CP) in normal aging. Morphological modifications of CP were observed by transmission electron microscope. Real-time RT-PCR was used to measure mRNA expressions of Aβ(42) and its transporters, which include low density lipoprotein receptor-related protein-1 and 2 (LRP-1 and -2), P-glycoprotein (P-gp) and the receptor for advanced glycation end-products (RAGE), at the CP epithelium in rats at ages of 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36 months. At the same time, the mRNA expressions of oxidative stress-related proteins were also measured. The results showed that a striking deterioration of the CP epithelial cells and increased Aβ(42) mRNA expression were observed in aged rats, and there was a decrease in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE mRNA expression and an increase in LRP-2, the CP epithelium Aβ influx transporter. Heme oxygenase-1 (HO-1) and caspase-3 expressions at the CP epithelium increased with age at the mRNA level. These results suggest the efficacy of the CP in clearing of Aβ deceases in normal aging, which results in the increase of brain Aβ accumulation. And excess Aβ interferes with oxidative phosphorylation, leads to oxidative stress and morphological structural changes. This in turn induces further pathological cascades of toxicity, inflammation and neurodegeneration process.

Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes

LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding on cleavage with a disintegrin and metalloproteinase 17 (ADAM17). A shedding mechanism is presumed to have a key role in the functions of LR11, but the evidence for this has not yet been demonstrated. Tetraspanin CD9 has been recently shown to regulate the ADAM17-mediated shedding of tumor necrosis factor-alpha and intercellular adhesion molecule-1 on the cell surface. Here, we investigated the role of CD9 on the shedding of LR11 in leukocytes. LR11 was not expressed in THP-1 monocytes, but it was expressed and released in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 macrophages (PMA/THP-1). Confocal microscopy showed colocalization of LR11 and CD9 proteins on the cell surface of PMA/THP-1. Ectopic neo-expression of CD9 in CCRF-SB cells, which are LR11-positive and CD9-negative, reduced the amount of sLR11 released from the cells. In contrast, incubation of LR11-transfected THP-1 cells with neutralizing anti-CD9 monoclonal antibodies increased the amount of sLR11 released from the cells. Likewise, the PMA-stimulated release of sLR11 increased in THP-1 cells transfected with CD9-targeted shRNAs, which was negated by treatment with the metalloproteinase inhibitor GM6001. These results suggest that the tetraspanin CD9 modulates the ADAM17-mediated shedding of LR11 in various leukemia cell lines and that the association between LR11 and CD9 on the cell surface has an important role in the ADAM17-mediated shedding mechanism.

Single-nucleotide polymorphisms of GSK3B, GAB2 and SORL1 in late-onset Alzheimer's disease: interactions with the APOE genotype

In this study, we investigated the associations between single-nucleotide polymorphisms in GAB2 (rs2373115), GSK3B (rs6438552) and SORL1 (rs641120) and Alzheimer's disease (AD), both alone and in combination with the APOE*4 allele.

Efeitos da quimioterapia neoadjuvante sobre os receptores de lipoproteínas no tecido tumoral em pacientes com carcinoma da mama localmente avançado / Effects of neoadjuvant chemotherapy on lipoprotein receptors in tumor tissues of patients with locally advanced breast cancer

Os tumores malignos apresentam um aumento da expressão dos receptores de lipoproteínas, devido ao aceleramento da proliferação celular com consequente aumento da necessidade de lípides para a síntese das membranas celulares. Esse aumento da expressão dos receptores de LDL no câncer pode ser utilizado para concentrar fármacos de ação antineoplásica em tecido tumoral, utilizando lipoproteínas ou nanoemulsões semelhantes a lipoproteínas como veículo. No presente estudo, foram investigados os efeitos da quimioterapia convencional na expressão dos receptores de LDL e LRP-1 em 16 pacientes com carcinoma de mama estádios II ou III, não candidatas à cirurgia conservadora e com indicação de tratamento quimioterápico neoadjuvante. A expressão dos receptores LDLR e LRP-1 foi avaliada por imunoistoquimica em tecido mamário normal e em tecido neoplásico antes e depois da quimioterapia neoadjuvante. Quatro pacientes que apresentaram resposta completa à quimioterapia foram retiradas da análise da expressão de receptores por não existir tumor no fragmento cirúrgico. Em relação ao LDLR, a expressão desse receptor no tecido neoplásico foi maior em comparação ao tecido normal em 8 das 11 pacientes. Após a quimioterapia, a expressão do receptor de LDL diminuiu em 6, aumentou em 4 e não se alterou em 2 pacientes. Do mesmo modo, a expressão do receptor LRP-1 no tecido tumoral estava aumentada em relação ao tecido normal em 4 pacientes das 12 avaliadas. Em comparação com o tecido tumoral antes da quimioterapia, a expressão do receptor LRP-1 diminuiu em 6, aumentou em 4 e permaneceu inalterada em 2 pacientes após a quimioterapia. Esses dados mostram que o efeito da quimioterapia na expressão dos receptores de lipoproteínas foi heterogêneo. A redução da expressão dos receptores não foi o padrão observado, o que indica que o uso de sistemas de carreamento de fármacos via receptores de LDL para o tratamento do câncer pode ser de grande importância...

Proliferative tumor cells present a high expression of LDL receptors due to accelerated mitosis rates which takes to increased need of lipids internalization for building new membranes. Upregulation of LDL receptors may be used as a gate to deliver anticancer drugs to tumor tissues using lipoproteins or artificial nanoemulsions as vehicle. This study investigated the effects of conventional chemotherapy on the expression of LDL and LRP-1 receptors in 16 patients with breast cancer in stage II or III who were not candidates to conservative surgery and with indication of neo-adjuvant chemotherapy. Expression of LDL and LRP-1 receptor was evaluated by immunohistochemistry in normal and neoplastic breast tissue before and after chemotherapy. For absence of tumor in the surgical fragments, 4 patients who presented complete response to chemotherapy were excluded from this analysis. In relation of LDLR, the expression in neoplastic tissue was higher than in normal tissue in 8 of 11 patients. After chemotherapy, LDL receptor expression diminished in 6, increased in 4 and unchanged in 2 patients. Expression of LRP-1 in tumor tissue was higher in 4 of 12 patients when compared to normal tissue. After chemotherapy, the expression of LRP-1 diminished in 6, increased in 4 and showed no difference in 2 patients. These data show that the chemotherapy effects on the tumor expression of LDL receptors were very heterogeneous. The diminution of the receptor expression is not the post-chemotherapy pattern, allowing the use of drug carrier systems that target cancer cells via the LDL receptor pathway. These results may contribute for the design of future clinical assays.

Hipercolesterolemia familiar heterocigota: diagnóstico molecular y terapia combinada. Caso clínico / Molecular diagnosis and combined lipid lowering therapy of heterozygous familial hypercholesterolemia: Report of one case

Heterozygous familial hypercholesterolemia affects one every 400 individuals, is caused by mutations in the LDL receptor gene and is associated with premature coronary artery disease. Nowadays, LDL cholesterol can be efficiently reduced with the new therapies to reduce blood lipids. We report a female patient who consulted in 1975, when she was 46 years old, for severe hypercholesterolemia. In 2003, a sample of leukocyte DNA was obtained and the uncommon 1705 + 1G >A mutation of the LDL receptor gene was detected. No mutations in the apolipoprotein B gene were found. The patient was treated successfully with simvastatin 80 mg/day and ezetimibe 10 mg/day and LDL cholesterol levels were reduced below 200 mg/dl.

Genomic structure of low density lipoprotein receptor related protein 5 gene / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To determine the genomic structure of low density lipoprotein receptor related protein 5 (LRP5) gene.</p><p><b>METHODS</b>cDNA sequence encoding LRP5 was used to screen genomic clones containing LRP5 gene by computer hybridization approach. By comparing the cDNA sequence of LRP5 with the genomic sequences, the genomic structure of LRP5 was determined, and then it was conformed by amplifying and sequencing the sequences of exons and splicing junction.</p><p><b>RESULTS</b>The genomic sequence of LRP5 gene was 131.6 kb in length, containing 23 exons and 22 introns. Three single nucleotide polymorphisms were detected within the coding sequences of LRP5 gene, namely A459G in exon 2, C2220T in exon 10 and G4416C in exon 21. Four polymorphic markers, D11S1917, D11S4087, D11S1337 and D11S4178, located in the 5' flank sequence, introns 1, 4, and 13 of the LRP5 gene, respectively.</p><p><b>CONCLUSION</b>The characterization of genomic structure of LRP5 gene allows the investigators to detect disease-causing mutation within the gene and further study the function of LRP5 gene.</p>