BBA - Molecular Basis of Disease (v.1762, #1)
Editorial Board (ii).
Lipopolysaccharides of Vibrio cholerae: III. Biological functions by S.N. Chatterjee; Keya Chaudhuri (1-16).
This review presents the salient features of the biological functions including the (i) endotoxic activities, (ii) antigenic properties, (iii) immunological responses to and (iv) phage receptor activities of the Vibrio cholerae lipopolysaccharides (LPS). The biological functions of the capsular polysaccharide (CPS) of V. cholerae have also been discussed briefly as a relevant topic. The roles of LPS and other extracellular polysaccharides in the (i) intestinal adherence and virulence of the vibrios and (ii) the biofilm formation by the organisms have been analysed on the basis of the available data. Every effort has been made to bring out, wherever applicable, the lacunae in our knowledge. The need for the continuous serogroup surveillance and monitoring of the environmental waters and the role of LPS in the designing of newer cholera vaccines has been discussed briefly in conclusion.
Keywords: Vibrio cholerae; Lipopolysaccharide (LPS); Capsular polysaccharide (CPS); Endotoxin, antigen (Ag); Antibody (Ab); Immunoglobulin (Ig); Phage receptor; Biofilm; Vaccine;
The importance and identification of regulatory polymorphisms and their mechanisms of action by Paul R. Buckland (17-28).
The search for the genetic variations underlying all human phenotypes is in its infancy but must be one of the long term goals of the scientific community. There is evidence that most, if not all human phenotypes, including illnesses are influenced by the genetic makeup of the individual. There are an estimated 11 million human genetic polymorphisms with a minor allele frequency >1% and possibly many times that number of rare sequence variants. The proportion of these sequence variants which have any functional effect is unknown but it is likely that the majority of those which influence illness lie outside of the amino acid coding regions of genes, and affect the regulation of gene expression—these are called rSNPs. Recent research suggests that about 50% of genes have one or more common rSNPs associated with them and probably most if not all genes have an rSNP within the human population. In the long term, determining which polymorphisms are potentially functional must be done bio-informatically using algorithms based upon experimental data. However, at the current time, the limited data that has been obtained does not allow the creation of such an algorithm. In vitro studies suggest that a large proportion of rSNPs lie within the core and proximal promoter regions of genes but it is not clear how the majority of these influence transcription, as they do not appear to be within any known transcription factor binding sites. However, promoter regions possess a number of sequence-dependent characteristics which make them distinct from the rest of the genome, namely stability, curvature and flexibility. Subtle changes to these features may underlie the mechanisms by which many polymorphisms exert their function.
Keywords: Genetic variation; Allelic expression; rSNP; DNA curvature; DNA flexibility;
HPRTSardinia: a new point mutation causing HPRT deficiency without Lesch–Nyhan disease by Antonello Cossu; Sandro Orrù; Gabriella Jacomelli; Carlo Carcassi; Licinio Contu; Silvia Sestini; Maria Rita Corradi; Giuseppe Pompucci; Aldo Carcassi; Vanna Micheli (29-33).
Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency always causing hyperuricemia presents various degrees of neurological manifestations, the most severe which is Lesch–Nyhan syndrome. The HPRT gene is situated in the region Xq26-q27.2 and consists of 9 exons. At least 300 different mutations at different sites in the HPRT coding region from exon 1 to exon 9 have been identified. A new mutation in the HPRT gene has been determined in one patient with complete deficiency of erythrocyte activity, with hyperuricemia and gout but without Lesch–Nyhan disease. Analysis of cultured fibroblasts revealed minimal residual HPRT activity mainly when guanine was the substrate. Genomic DNA sequencing demonstrated patient's mother heterozygosity for the mutation and no mutation in her brother. The mutation consists in a C→T transversion at cDNA base 463 (C463T) in exon 6, resulting in proline to serine substitution at codon 155 (P155S). This mutation had not been reported previously and has been designated HPRTSardinia. The mutation identified in this patient allows some expression of functional enzyme in nucleated cells such as fibroblasts, indicating that such cell type may add further information to conventional blood analysis. A multicentre survey gathering patients with variant neurological forms could contribute to understand the pathophysiology of the neurobehavioral symptoms of HPRT deficiency.
Keywords: Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency; Lesch–Nyhan syndrome; Human mutation, purine and pyridine nucleotide;
Identification of a pre-mRNA splicing factor, arginine/serine-rich 3 (Sfrs3), and its co-expression with fibronectin in fetal and postnatal rabbit airway mucosal and skin wounds by Ha-Sheng Li-Korotky; Patricia A. Hebda; Lori A. Kelly; Chia-Yee Lo; Joseph E. Dohar (34-45).
Fibronectin (FN) is a multi-functional, adhesion protein and involved in multi-steps of the wound healing process. Strong evidence suggests that FN protein diversity is controlled by alternative RNA splicing; a coordinated transcription and RNA processing that is development-, age-, and tissue/cell type-regulated. We previously demonstrated that fetal rabbit airway mucosal healing is regenerative and scarless. Expression, regulation, and biological function of the FN gene and various spliced forms in this model are unknown. Airway and skin incisional wounds were made in fetal (gestation days 21–23), weanling (4–6 weeks) and adult (>6 months) rabbits. Non-wounded and wounded tissues were collected at 12 h (all age groups), 24 h and 48 h (weanling only) post-wounding. Expression profiles were obtained using mRNA differential display and cDNAs of interest were cloned, sequenced and validated by real-time PCR. Here, we report two rabbit cDNAs that showed similar expression patterns after wounding. One encodes a rabbit fibronectin gene, Fn1, and another shares a high sequence homology to a human pre-mRNA splicing factor, arginine/serine-rich 3 (Sfrs3), coding for a RNA binding protein, SRp20. Both Fn1 and Sfrs3 mRNAs were suppressed in fetal wounds but induced in postnatal wounds 12 h post-wounding. The increased levels of both Fn1 and Sfrs3 transcripts were sustained up to 48 h in weanling airway mucosal wounds. The augmentations of the two genes in postnatal airway mucosal wounds were more prominent than that in skin wounds, indicating that the involvement of Sfrs3 and Fn1 genes in postnatal airway mucosal wounds is tissue-specific. Literature provides evidence that SRp20 is indeed involved in the alternative splicing of FN and that the embryonic FN variants reappear during adult wound healing. A connection between the enhanced molecular activity of Sfrs3 and the regulation of the FN gene expression through alternative splicing during the early events of postnatal airway mucosal wound repair was proposed.
Keywords: Airway mucosa; Fetal wound healing; Fibronectin; Differential gene expression; Splicing factor; SRp20;
Antigen presenting cells (APCs) from thermally injured and/or septic rats modulate CD4+ T cell responses of naive rat by Nadeem Fazal; Syed Raziuddin; Mehdi Khan; Walid M. Al-Ghoul (46-53).
Regulation of immune response is marked by complex interactions among the cells that recognize and present antigens. Antigen presenting cells (APCs), the antigen presenting cell component of the innate immune response plays an important role in effector CD4+ T cell response. Thermal injury and/or superimposed sepsis in rats' leads to suppressed CD4+ T cell functions. We investigated modulations of CD4+ T cell function by APCs (purified non-T cells) from thermally injured and/or septic rats. Rats were subjected to 30% total body surface area scald burn or exposed to 37 °C water (Sham burn) and sepsis was induced by cecal-ligation and puncture (CLP) method. At day 3 post-injury animals were sacrificed and CD4+ T cells and APCs from mesenteric lymph nodes (MLN) were obtained using magnetic microbead isolation procedure. APCs from injured rats were co-cultured with sham rat MLN CD4+ T cells and proliferative responses (thymidine incorporation), phenotypic changes (Flow cytometry), IL-2 production (ELISA) and CTLA-4 mRNA (RT-PCR) were determined in naive rat CD4+ T cells. The data indicate that APCs from thermally injured and/or septic rats when co-cultured with CD4+ T cells suppressed CD4+ T cell effector functions. This lack of CD4+ T cell activation was accompanied with altered co-stimulatory molecules, i.e., CD28 and/or CTLA-4 (CD152). In conclusion, our studies indicated that defective APCs from thermally injured and/or septic rats modulate CD4+ T cell functions via changes in co-stimulatory molecules expressed on naive CD4+ T cells. This altered APC: CD4+ T cell interaction leads to suppressed CD4+ T cell activation of healthy animals.
Keywords: Antigen presentation; Dendritic cell; Burn injury; Sepsis; IL-2 production; Mesenteric lymph node; Costimulatory molecule; CD28; CTLA-4;
Collagen type IX and HNK-1 epitope in tears of patients with pseudoexfoliation syndrome by M. Assouti; D.H. Vynios; S. Th. Anagnostides; G. Papadopoulos; C.D. Georgakopoulos; S.P. Gartaganis (54-58).
Pseudoexfoliation syndrome (PEX) is an age-related condition, which may cause open-angle glaucoma and has increasing interest since it seems to affect additional human tissues, i.e., cardiovascular tissue, skin, and still lacks elucidated pathogenesis. Collagen type IX and HNK-1 epitope have been considered characteristic constituents of the aqueous humour of PEX patients, since their amounts were increased in PEX aqueous humour compared to normal eyes. Since it has been proposed that the initial manifestations of PEX syndrome occur in conjunctiva, the present study was undertaken to investigate the presence of the same antigens in tears of PEX patients and their possible use as the biochemical markers for early diagnosis. Tears of PEX patients and healthy individuals were subjected to western blotting analysis for various basement membrane components identified in aqueous humour. It was found that collagen type IX and HNK-1 epitope were present in tears, the amount of the former being increased 2.7 times compared to normal (P < 0.05), surprisingly high as compared with total protein or lysozyme activity in tears, which were found to be increased in PEX patients about 25% with no statistical differences (P ≈ 0.4). The results suggest the possible use of tears' collagen type IX for the diagnosis of PEX syndrome.
Keywords: Proteoglycan; Glycosaminoglycan; Glycoprotein; Eye; Aqueous humour; Human disease;
Frequency of hemochromatosis gene (HFE) mutations in Russian healthy women and patients with estrogen-dependent cancers by Tatiana V. Kondrashova; Kazuo Neriishi; Sadayuki Ban; Tatiana I. Ivanova; Lyudmila I. Krikunova; Nataliya I. Shentereva; Iya A. Smirnova; Irina A. Zharikova; Marina V. Konova; Senjun Taira; Anatoly F. Tsyb (59-65).
Possible association between the C282Y and H63D mutations in the HFE gene and estrogen-dependent cancer risk was assessed. Genotyping was performed using PCR amplification followed by digestion of products with specific restrictases. In a population of 260 healthy women (permanent residents of the southwest European Russia), mutant allele frequencies at the C282Y and H63D sites were evaluated as 3.3 and 16.3%, respectively. In patients with breast, ovarian, and endometrial cancer, C282Y frequencies were also low (1.0, 1.3, and 3.8%, respectively), and no cancer risk associated with the C282Y mutation was found. Odds ratios for breast cancer risk associated with the H63D mutation increased significantly with age: 0.5 in women below 48 years old, 1.0 in a range of 48–57 years, and 4.4 in older women (P trend = 0.002). The latter value was statistically significant (95% CI, 1.4–14.1), indicating that women bearing the H63D mutation may be at an increased breast cancer risk at an age above 57 years. Preliminary results obtained in patients with two other estrogen-dependent malignancies revealed the same tendency to OR increase with age in ovarian cancer patients (P trend = 0.008), but no age-related OR differences in endometrial cancer patients.
Keywords: HFE mutation; Iron metabolism; Oxidative stress; Cancer risk; Age;
Ca2+-independent binding and cellular expression profiles question a significant role of calmyrin in transduction of Ca2+-signals to Alzheimer's disease-related presenilin 2 in forebrain by Magdalena Blazejczyk; Urszula Wojda; Adam Sobczak; Christina Spilker; Hans-Gert Bernstein; Eckart D. Gundelfinger; Michael R. Kreutz; Jacek Kuznicki (66-72).
The interaction between the EF-hand Ca2+-binding protein calmyrin and presenilin 2 (PS2) has been suggested to play a role in Alzheimer's disease (AD). We now report that calmyrin binds specifically endogenous PS2 and not PS1. However, binding appears to be Ca2+-independent and calmyrin does not exhibit a Ca2+-dependent translocation to intracellular membranes as demonstrated in a Ca2+-myristoyl switch assay. Moreover, calmyrin is only present at very low levels in brain areas associated with the onset of AD. In rat, forebrain calmyrin is localized only in a subset of principal neurons, similarly as in human forebrain. Finally, subcellular fractionation demonstrates only a limited overlap of calmyrin and PS2 at neuronal membranes. We therefore conclude that calmyrin will not contribute significantly as a Ca2+-sensor that transduces Ca2+-signaling events to PS2 in forebrain.
Keywords: EF-hand calcium-binding protein; Calmyrin; CIB1; KIP1; Presenilin 2; Alzheimer's disease;
The Wnt pathway is active in a small subset of pancreas cancer cell lines by Judit Pujal; Gabriel Capellá; Francisco X. Real (73-79).
Activation of the Wnt pathway plays an important role in the development of a wide variety of tumor types. Two genes involved in the activation of this pathway in tumors are Adenomatous Polyposis Coli (APC) and β-catenin. Here, we analyze the activity of the Wnt pathway in cultured cells derived from ductal and acinar pancreatic adenocarcinomas using a reporter assay dependent on the activity of the β-catenin/Tcf4 complex. We find that low-level Wnt activity can be detected in several pancreas cancer lines. High levels of reporter activity were detected exclusively in RWP-1 cells. These cells display nuclear β-catenin and express a truncated APC protein resulting from a CAA>TAA mutation (Q1303X). Expression of a dominant negative Tcf4 protein inhibited proliferation of RWP-1 cells but not in other lines lacking β-catenin-dependent reporter activity, supporting the functional relevance of this mutation. Our findings indicate that activation of the Wnt pathway may play a role in a small subset of ductal pancreatic cancers. Alternatively, RWP-1 cells may have been derived from a tumor arising in a structure adjacent to the pancreas such as the biliary tract or the Ampulla of Vater. Additional studies on the role of Wnt pathway components in the development/progression of tumors of the peripancreatic region merit consideration.
Keywords: Pancreas cancer; APC; Beta catenin; Bile tract cancer; RWP-1 cell;
VSL#3 probiotic preparation has the capacity to hydrolyze gliadin polypeptides responsible for Celiac Sprue probiotics and gluten intolerance by Maria De Angelis; Carlo G. Rizzello; Alessio Fasano; Maria G. Clemente; Claudio De Simone; Marco Silano; Massimo De Vincenzi; Ilario Losito; Marco Gobbetti (80-93).
The native structure and distribution of gliadin epitopes responsible for Celiac Sprue (CS) may be influenced by cereal food processing. This work was aimed at showing the capacity of probiotic VSL#3 to decrease the toxicity of wheat flour during long-time fermentation. VSL#3 (109 cfu/ml) hydrolyzed completely the α2-gliadin-derived epitopes 62–75 and 33-mer (750 ppm). Two-dimensional electrophoresis, immunological (R5 antibody) and mass spectrometry analyses showed an almost complete degradation of gliadins during long-time fermentation of wheat flour by VSL#3. Gliadins non-hydrolyzed during fermentation by VSL#3 were subjected to peptic-tryptic (PT) digestion and analyzed by CapLC-ESI-Q-ToF-MS (Capillary Liquid Chromatography-Electrospray Ionization-Quadrupole-Time of Flight-Mass Spectrometry). Search for several epitopes showed the only presence of α2-gliadin-fragment 62–75 at a very low concentration (sub-ppm range). Compared to IEC-6 cells exposed to intact gliadins extracted from the chemically acidified dough (control), VSL#3 pre-digested gliadins caused a less pronounced reorganization of the intracellular F-actin which was mirrored by an attenuated effect on intestinal mucosa permeability. The release of zonulin from intestinal epithelial cells treated with gliadins was considerably lower when digested with VSL#3. Agglutination test on K 562 (S) cells showed that the PT-digest of wheat flour treated with VSL#3 increased the Minimal Agglutinating Activity of ca. 100 times. Wheat proteins were extracted from doughs and subjected to PT digestion. Compared to PT-digest from chemically acidified dough, celiac jejunal biopsies exposed to the PT-digest from the dough fermented by VSL#3 did not show an increase of the infiltration of CD3+ intraepithelial lymphocytes. Proteolytic activity by probiotic VSL#3 may have an importance during food processing to produce pre-digested and tolerated gliadins for increasing the palatability of gluten-free products.
Keywords: Celiac Sprue; Probiotic; Wheat flour; Proteolysis; Gliadin; Zonulin; CD3+;
Early glycation products of endothelial plasma membrane proteins in experimental diabetes by Sarah Nguyen; Mirela Pascariu; Lucian Ghitescu (94-102).
The participation of glucose and two intermediates of glucose metabolism: glucose-6-phosphate (G6P) and glyceraldehyde-3-phosphate (Gald3P) to the formation of early glycation products was comparatively evaluated in the endothelial plasma membrane of streptozotocin-induced diabetic rats. Antibodies risen to a carrier protein reductively glycated by each of the sugars mentioned above were used to probe by immunoblotting the proteins of the lung microvascular endothelium plasmalemma purified from normal and diabetic rats. The amount of glycated endothelial plasma membrane proteins was below the limit of detection in normoglycemic animals but increased dramatically in diabetic animals for glucose and G6P. In contrast, no signal was found in diabetic rats for Gald3P, indicating that either the contribution of this phosphotriose to the glycation of intracellular proteins is negligible in vivo, or the Schiff base generated by this sugar transforms very rapidly into products of advanced glycation. Globally, the endothelial plasma membrane proteins bound on average 300 times more glucose than G6P proving that, in spite of its low in vitro potency as glycating agent, glucose represents the main contributor to the intracellular formation of early glycation products. The most abundant glycated proteins of the lung endothelial plasma membrane were separated by two dimensional electrophoresis and identified by mass spectrometry.
Keywords: Endothelium; Plasma membrane; Glycation; Protein; Diabetes;
Age-related alterations in expression of apoptosis regulatory proteins and heat shock proteins in rat skeletal muscle by Linda Chung; Yuk-Chow Ng (103-109).
Aging of skeletal muscle is often accompanied by muscle atrophy and it appears that apoptosis plays an important role in this process. The detailed mechanism(s) is not completely understood, however. In this study, we examined expression of the apoptosis regulatory proteins as well as the heat shock proteins, which have been shown to modulate the apoptotic process in certain cell types, in order to more completely elucidate apoptotic signaling in aged skeletal muscle. To more specifically identify alterations that are likely to be the result of aging, we compared 16-month-old middle-aged (MD) and 29-month-old senescent (SE) male Fischer 344 × Brown Norway rats in our study. Our results show that the degree of DNA laddering was higher in SE compared to MD rats. Using total tissue homogenates we examined the level of expression of several apoptosis-related proteins in two categories: mitochondria-associated proteins and caspases. Of the mitochondria-associated proteins, the levels of p53 showed a significant increase in SE compared to MD rats. There was also a significant increase in the expression of Bax, Bcl-2 and Apaf-1 in SE rats over that of MD rats; cytochrome c and AIF levels remained unchanged, however. Regarding the caspases, there were increases in the levels of pro-caspases-12 and -7 and cleaved caspase-9, although the levels of pro- and cleaved caspase-3 as well as cleaved caspase-12 remained unchanged. Furthermore, our results showed significant increases in HSP27, HSP60, and the inducible HSP70. These data show that in rat skeletal muscle increased apoptosis occurs between middle-age and senescence, indicating an aging-related increase in apoptosis in skeletal muscle. The involvement of different apoptotic pathways in the aging process is suggested by the selective alterations in the apoptosis regulatory proteins. The increased expression of the HSPs suggests a relationship between HSPs and the aging-related apoptotic process.
Keywords: Apoptosis; Skeletal muscle; Aging; Heat shock proteins;
Role of tyrosine-57 and -65 in membrane-damaging and sphingomyelinase activities of Clostridium perfringens alpha-toxin by Masahiro Nagahama; Akiko Otsuka; Jun Sakurai (110-114).
Clostridium perfringens alpha-toxin (370 residues) is a major virulence factor in the pathogenesis of gas gangrene. The toxin is composed of an N-terminal domain (1–250 residues) where lies the catalytic site and a C-terminal domain (251–370 residues), the Ca2+-binding domain, responsible for binding to membranes. The role of Tyr-57 and Tyr-65 close to the catalytic pocket (site) in the N-domain was investigated. Replacement of Tyr-57 and -65 with alanine, leucine, or phenylalanine did not affect the sphingomyelinase activity of the toxin for sodium deoxycholate-solubilized shingomyelin. However, the substitution of Tyr-57 and -65 with alanine or leucine resulted in a radical reduction in the hemolysis of sheep erythrocytes, the release of carboxyfluorescein from shingomyelin-cholesterol (1:1) liposomes, and a significant decrease in binding to the liposomes. The binding of variant toxins, Y57C/C169L and Y65C/C169L, labeled with the environmentally sensitive fluorophore, acrylodan, to the liposomes suggested insertion of the variants in a hydrophobic environment in the bilayer. These observations suggested that Tyr-57 and -65 play a role in the penetration of the toxin into the bilayer of membranes and access of the catalytic site to sphingomyelin in membranes, but do not participate in the enzymatic activity.
Keywords: Clostridium perfringens; Alpha-toxin; Hemolytic activity; Sphingomyelinase; Liposome;
Decreased agonist-stimulated mitochondrial ATP production caused by a pathological reduction in endoplasmic reticulum calcium content in human complex I deficiency by Henk-Jan Visch; Werner J.H. Koopman; Anouk Leusink; Sjenet E. van Emst-de Vries; Lambertus W.P.J. van den Heuvel; Peter H.G.M. Willems; Jan A.M. Smeitink (115-123).
Although a large number of mutations causing malfunction of complex I (NADH:ubiquinone oxidoreductase) of the OXPHOS system is now known, their cell biological consequences remain obscure. We previously showed that the bradykinin (Bk)-induced increase in mitochondrial [ATP] ([ATP]M) is significantly reduced in primary skin fibroblasts from a patient with an isolated complex I deficiency. The present work addresses the mechanism(s) underlying this impaired response. Luminometry of fibroblasts from 6 healthy subjects and 14 genetically characterized patients expressing mitochondria targeted luciferase revealed that the Bk-induced increase in [ATP]M was significantly, but to a variable degree, decreased in 10 patients. The same variation was observed for the increases in mitochondrial [Ca2+] ([Ca2+]M), measured with mitochondria targeted aequorin, and cytosolic [Ca2+] ([Ca2+]C), measured with fura-2, and for the Ca2+ content of the endoplasmic reticulum (ER), calculated from the increase in [Ca2+]C evoked by thapsigargin, an inhibitor of the ER Ca2+ ATPase. Regression analysis revealed that the increase in [ATP]M was directly proportional to the increases in [Ca2+]C and [Ca2+]M and to the ER Ca2+ content. Our findings provide evidence that a pathological reduction in ER Ca2+ content is the direct cause of the impaired Bk-induced increase in [ATP]M in human complex I deficiency.
Keywords: Complex I deficiency; Mitochondria; Bradykinin; ER calcium content; ATP;
Inhibition of cytokine-induced prostanoid biogenesis by phytochemicals in human colonic fibroblasts by Wendy R. Russell; Janice E. Drew; Lorraine Scobbie; Garry G. Duthie (124-130).
Many of the inflammatory pathways regulating the production of prostanoids are implicated in the development of colon cancer. Diets rich in fruits and vegetables are associated with decreased rates of colon cancer and this may reflect anti-inflammatory properties of some phytochemicals in plant-based foods. In order to ascertain which of the many dietary compounds may be protective, a cell-based screening method was established to determine their effects on the production of prostanoids. By up-regulating prostaglandin H synthase-2 in human colonic fibroblast cells with cytokines, we have investigated the potential protective effect of a structurally related group of phytochemicals on prostanoid biogenesis. Several of the compounds significantly inhibited prostanoid biogenesis, by up to 81% and others enhanced prostanoid production. All of the compounds that enhanced prostanoid production belonged to the hydroxylated benzoic acid family and good correlation was observed with their redox activity and the ability to enhance prostanoid production. Common structural features of the inhibitors were the presence of 4-hydroxyl and 3-methoxyl substituents on the aromatic ring and/or the presence of a three-carbon side-chain on C1.
Keywords: Colon cancer; Prostaglandin H synthase; Cyclooxygenase; Inflamation; IL-1β; Phenylpropanoid;
Phospholipid transfer protein activity is associated with inflammatory markers in patients with cardiovascular disease by Marian C. Cheung; B. Greg Brown; Emily K. Marino Larsen; Andrew D. Frutkin; Kevin D. O'Brien; John J. Albers (131-137).
Plasma phospholipid lipid transfer protein (PLTP) has several known key functions in lipoprotein metabolism. Recent studies suggest that it also may play a role in the inflammatory response. Inflammatory cell activity contributes to the development of atherosclerosis. To seek further evidence for the association of PLTP with inflammation, we studied the relationship between PLTP activity and five inflammatory markers [C-reactive protein (CRP), serum amyloid A (SAA), interleukin 6 (IL-6), white blood cells (WBC), and fibrinogen] in 93 patients with low HDL and cardiovascular disease (CVD). Plasma PLTP activity had the strongest correlation with CRP (r = 0.332, P < 0.001) followed by SAA (r = 0.239, P = 0.021). PLTP, CRP, and SAA were significantly associated with body mass index (BMI), insulin or glucose, apolipoprotein (apo) B, and/or apo E level (r = 0.264–0.393, P < 0.01). PLTP, SAA, and IL-6 also were associated with the concentration of HDL particles without apo A-II [Lp(A-I)](r = 0.373–0.472, P < 0.005, n = 56), but not particles with apo A-II. Smoking was associated with increased PLTP activity, CRP, and WBC, and hypertension with increased PLTP activity. In linear models, CRP remained significantly associated with PLTP after adjustment of CVD risk factors and insulin resistance. Also, much of the variability of plasma PLTP activity was explained by CRP, BMI, Lp(A-I), smoking, glucose, and blood pressure. These findings show for the first time that plasma PLTP activity is associated positively with CRP in CVD, a state of chronic inflammation.
Keywords: Phospholipid transfer protein; Inflammatory marker; Cardiovascular disease;