Maria Lopes-virella - Academia.edu (original) (raw)

Papers by Maria Lopes-virella

Atherosclerosis, Oct 1, 2008

Journal of Diabetes and Its Complications, Oct 1, 2019

Background:To determine if serum pigment epithelium-derived factor (PEDF) levels predict cardiova... more Background:To determine if serum pigment epithelium-derived factor (PEDF) levels predict cardiovascular events, renal dysfunction and mortality in the Veterans Affairs Diabetes Study (VADT).Methods:PEDF was evaluated in relation to subsequent cardiovascular outcomes, mortality, and renal dysfunction (defined as urinary albumin creatinine ratio (ACR) ≥300 mg/g), or chronic kidney disease (CKD) stages 3 (eGFR<60 ml/min) or 4 (eGFR<60 and <30 ml/min respectively). PEDF was measured by ELISA on sera from 881 participants collected a median (range) of 1.7 (0–5.0) years post-baseline, and later, from 832 participants 4.0 (1.5–6.9) years post-baseline.Results:In 743 participants, PEDF was measured at both time-points. PEDF increased over time from (mean±SD) 10.5±4.03 to 11.0±4.86 ng/ml (paired t-test p=0.0092). Lower eGFR (p<0.01), higher serum creatinine (p<0.01) and urinary ACR (p<0.01) were associated with increasing PEDF. Multivariate event time models included either one or two follow-up windows (i.e., between first and second PEDF measures; and, when available, from second PEDF measure until study-end). PEDF tertiles were not associated with cardiovascular events, but were significantly associated with all-cause mortality [HR=2.00 (1.03, 3.89) comparing first to third tertile] in models adjusted for age, minority status, VADT treatment arm and prior cardiovascular event status. Higher PEDF levels also associated with development of kidney dysfunction with adjusted HRs (95% CI comparing third to first PEDF tertiles: 2.74 (1.71, 4.39) for stage 3 CKD; and 3.84 (95% CI: 1.17, 12.5) for stage 4 CKD.Conclusions:Over 2-years, higher serum PEDF levels predicted advanced nephropathy in patients with type 2 diabetes.

Clinical and Vaccine Immunology, Jul 1, 2003

Two decades ago, well before the inflammatory nature of arteriosclerosis was generally accepted, ... more Two decades ago, well before the inflammatory nature of arteriosclerosis was generally accepted, several groups reported the finding of immunoglobulins and various complement components in atheromatous plaques of humans and rabbits (12, 42, 69). A decade later apolipoprotein B (ApoB) extracted from atheromatous lesions was found to react with monoclonal antibodies against malondialdehyde (MDA)-and 4-hydroxynonenal (HNE)-lysine, two common modifications of oxidized low-density lipoprotein (oxLDL) (38, 73), and immunoglobulin G (IgG) isolated from rabbit and human atherosclerotic lesions showed reactivity with MDA-and coppermodified LDL (74). These seminal observations represent arguably the best evidence available for the involvement of modified LDL antibodies and in situ formed antigen-antibody complexes in the induction and/or perpetuation of chronic vascular inflammation. It also gave a solid rationale for expanding study of the immunogenic properties of modified forms of LDL and to the development of methods for their assay in serum. From the immunological point of view, oxLDL has been studied in most detail. LDL oxidation affects both the lipid and protein components of LDL. Reactive aldehyde products result from the oxidation of polyunsaturated fatty acids and include MDA and 4-HNE, capable of attaching covalently to the ε-amino groups of lysine residues of ApoB (49, 50, 73). These modifications are present in copper-oxidized LDL, which was found to have structural and functional properties similar to those of LDL isolated from atherosclerotic plaques (73) and to react with monoclonal antibodies produced in guinea pigs against MDA and HNE-lysine (38, 73). Detailed investigations have also been carried out with advanced glycosylation end product-modified LDL (AGE-LDL). Advanced glycosylation involves a chain of chemical reactions that starts with the nonenzymatic addition of reducing sugars to protein amino groups (Schiff base, Amadori adducts). If the half-life of a protein is sufficiently long, additional reactions take place leading to the formation of a heterogeneous family of sugar-amino acid adducts collectively known as "advanced glycosylation end products" (AGE) (43). LDL, like most plasma proteins, is susceptible to AGE modification (45). AGE-modified proteins are immunogenic (18), a property that

Atherosclerosis, Feb 1, 2009

Recent Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Co... more Recent Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and other clinical studies have reported that glucose control in patients with diabetes leads to a significant reduction of cardiovascular events and atherosclerosis, indicating that hyperglycemia plays an essential role in cardiovascular disease in diabetic patients. Although several mechanisms by which hyperglycemia promotes atherosclerosis have been proposed, it remains unclear how hyperglycemia promotes atherosclerosis by interaction with inflammatory cytokines. To test our hypothesis that hyperglycemia interplays with interferon gamma (IFNγ), a key factor involved in atherosclerosis, to up-regulate the expression of genes such as matrix metalloproteinases (MMPs) and cytokines that are involved in plaque destabilization, U937 macrophages cultured in medium containing either normal or high glucose were challenged with IFNγ and the expression of MMPs and cytokines were then quantified by real-time PCR and ELISA. Results showed that high glucose and IFNγ had a synergistic effect on the expression of MMP-1, MMP-9 and IL-1β. High glucose also enhanced IFNγ-induced priming effect on LPS-stimulated MMP-1 secretion. Furthermore, high glucose and IFNγ exert the synergistic effect on MMP-1 expression by enhancing STAT1 phosphorylation and STAT1 transcriptional activity. In summary, this study revealed a novel mechanism potentially involved in diabetes-promoted cardiovascular disease.

PLOS ONE

GPR40, a G protein-coupled receptor for free fatty acids (FFAs), is considered as a therapeutic t... more GPR40, a G protein-coupled receptor for free fatty acids (FFAs), is considered as a therapeutic target for type 2 diabetes mellitus (T2DM) since GPR40 activation in pancreatic beta cells enhances glucose-stimulated insulin secretion. Nonalcoholic fatty liver disease (NAFLD) is a common complication of T2DM or metabolic syndrome (MetS). However, the role of GPR40 in NAFLD associated with T2DM or MetS has not been well established. Given that it is known that cholesterol and FFAs are critically involved in the pathogenesis of nonalcoholic steatohepatitis (NASH) and LDL receptor (LDLR)-deficient mice are a good animal model for human hyperlipidemia including high cholesterol and FFAs, we generated GPR40 and LDLR double knockout (KO) mice in this study to determine the effect of GPR40 KO on hyperlipidemia-promoted NASH. We showed that GPR40 KO increased plasma levels of cholesterol and FFAs in high-fat diet (HFD)-fed LDLR-deficient mice. We also showed that GPR40 KO exacerbated HFD-indu...

This article cites 33 articles, 13 of which can be accessed free

Clinical Diagnostic Laboratory Immunology, 1998

As part of our ongoing effort to develop a standardized competitive enzyme immunoassay for human ... more As part of our ongoing effort to develop a standardized competitive enzyme immunoassay for human autoantibodies to oxidized low-density lipoprotein (oxLDL), we have generated a reference human antibody standard and revised some of the conditions of the assay. The preparation of the standard involved purification of human anti-oxLDL antibodies by affinity chromatography using immobilized oxLDL. The total concentration of antibody in this purified human oxLDL antibody was established by adding the concentrations of immunoglobulin G (IgG), IgA, and IgM determined in the standard by radial immunodiffusion. The isolated antibody was used to calibrate a whole human serum standard, which was used to calibrate the assays to detect antibody in serum samples. We also revisited the general conditions for performance of our competitive assay. We determined that 1/20 was the ideal dilution for performing the absorption step, and that 1/20 and 1/40 were optimal dilutions to assay oxLDL antibody i...

Diabetes, 2019

We investigated whether the composition of modified forms of LDL in circulating immune complexes ... more We investigated whether the composition of modified forms of LDL in circulating immune complexes (LDL-ICs) was associated with cardiovascular disease (CVD) outcomes, including any CVD, major adverse cardiac and cerebrovascular events (MACCE), myocardial infarction (MI), and coronary artery disease, in type 1 diabetes (T1D). Our results demonstrate that the baseline levels of oxidized LDL (oxLDL), MDA-modified LDL (MDA-LDL), and advanced glycosylation–modified LDL (AGE-LDL) in circulating ICs were associated with the four CVD outcomes in unadjusted models, and adjustment by age and mean HbA1c only resulted in minimal reduction of these associations. After adjustments were made for other cardiovascular risk factors, particularly LDL cholesterol, oxLDL-IC and MDA-LDL-IC remained independently associated with the risk of CVD, and oxLDL-IC was independently associated with the risk of MACCE and MI. In the majority of cases, the baseline levels of modified LDL-IC (measured many years befo...

Journal of Lipid Research, 2019

Apolipoproteins APOB, APOC3, and APOE, and apolipoprotein-defined lipoprotein subclasses (ADLS; b... more Apolipoproteins APOB, APOC3, and APOE, and apolipoprotein-defined lipoprotein subclasses (ADLS; based on qualitative apolipoprotein complement) have been associated with dyslipidemia and cardiovascular disease (CVD). Our main objective was to define associations of serum apolipoproteins and ADLS with 'any CVD' and 'major atherosclerotic cardiovascular events' (MACE) in a prospective study of T1D. Serum apolipoproteins and ADLS (14 biomarkers in total) were measured in sera (obtained 1997-2000) from a subset (n=465) of the Epidemiology of Diabetes Interventions and Complications (EDIC) cohort. Prospective associations of 'any CVD' (myocardial infarction, stroke, confirmed angina, silent MI, revascularization, or congestive heart failure) and MACE (fatal or nonfatal myocardial infarction or stroke), over 5942 and 6180 patient-years follow-up respectively, were investigated using Cox proportional hazards models, unadjusted and adjusted for risk factors. During 15 years follow-up, 50 'any CVD' and 24 MACE events occurred. Nominally significant positive univariate associations with 'any CVD' were APOB, APOC3 and its sub-fractions [heparin precipitate (HP), heparin soluble (HS)], and ADLS-defined Lp-B. In adjusted analyses, APOC3-HS remained nominally significant. Nominally significant positive univariate associations with MACE were APOC3 and sub-fractions, and Lp-B:C; those with total APOC3 and APOC3-HS persisted in adjusted analyses. However, these associations did not reach significance after adjustment for multiple testing. There were no significant associations of APOA1, APOA2, APOE, or other ADLS with either 'any CVD' or MACE. These hypothesis-generating data suggest that total serum APOC3 and APOC3 in HDL are potentially important predictive biomarkers for 'any CVD' and MACE in T1D adults.

Atherosclerosis, 2017

Background and aims-Either lipopolysaccharide (LPS) or high-fat diet (HFD) enriched with saturate... more Background and aims-Either lipopolysaccharide (LPS) or high-fat diet (HFD) enriched with saturated fatty acid (SFA) promotes atherosclerosis. In this study, we investigated the effect of LPS in combination with SFA-rich HFD on atherosclerosis and how LPS and SFA interact to stimulate inflammatory response in vascular endothelial cells. Methods-Low-density lipoprotein receptor-deficient (LDLR −/−) mice were fed low-fat diet (LFD), HFD with low palmitic acid (PA) (LP-HFD), or HFD with high PA (HP-HFD) for 20 weeks. During the last 12 weeks, half mice received LPS and half received PBS. After treatment, metabolic parameters and aortic atherosclerosis were analyzed. To understand the underlying mechanisms, human aortic endothelial cells (HAECs) were treated with LPS and/or PA and proinflammatory molecule expression was quantified. Results-Metabolic study showed that LPS had no significant effect on cholesterol, triglycerides, free fatty acids, but increased insulin and insulin resistance. Both LP-HFD and HP-HFD increased body weight and cholesterol while LP-HFD increased glucose and HP-HFD increased triglycerides, insulin, and insulin resistance. Analysis of aortic atherosclerosis showed that HP-HFD was more effective than LP-HFD in inducing atherosclerosis and LPS in combination with HP-HFD increased atherosclerosis in the thoracic aorta, a less common site for atherosclerosis, as compared with LPS or HP-HFD. To understand the mechanisms, results

Molecular Immunology, 2011

Studies have demonstrated that TLR4 and TLR2 expression by monocytes and the blood levels of TLR4... more Studies have demonstrated that TLR4 and TLR2 expression by monocytes and the blood levels of TLR4 and TLR2 ligand in diabetic patients are significantly incased compared to nondiabetic patients, indicating that more monocytes in diabetic patients may have coactivation of TLR4 and TLR2. Although it has been shown that either TLR4 or TLR2 activation leads to increased expression of proinflammatory cytokines, the effect of coactivation of TLR2 and TLR4 in mononuclear cells on proinflammatory cytokine expression and the underlying molecular mechanisms remain largely unknown. In this study, we found that while TLR1, TLR2, TLR4 and TLR6 were expressed by U937 mononuclear cells, TLR4 was expressed at the highest level. Interestingly, results showed that while activation of either TLR4 or TLR2/6 (TLR2 dimerized with TLR6), but not TLR2/1 (TLR2 dimerized with TLR1), significantly increased IL-6 expression by U937 mononuclear cells, coactivation of TLR4 and TLR2/6, but not TLR4 and TLR2/1, led to a further augmentation on IL-6 expression by increasing IL-6 transcriptional activity, but not mRNA stability. To explore the signaling mechanisms involved in the augmentation, we found that p38 MAPK and NFκB pathways, but not ERK and JNK pathways, were required for the augmentation of IL-6 expression by coactivation of TLR4 and TLR2/6. Furthermore, we found that coactivation of TLR4 and TLR2/6 increased p38 phosphorylation, but not NFkB activity, as compared to activation of TLR4 or TLR2/6 alone. Taken together, this study showed that coactivation of TLR4 and TLR2/6 coordinates an additive augmentation of IL-6 gene transcription via p38 MAPK pathway in U937 mononuclear cells.

PLoS ONE, 2010

Background: Oxidized low-density lipoproteins (oxLDL) and oxLDL-containing immune complexes (oxLD... more Background: Oxidized low-density lipoproteins (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to formation of lipid-laden macrophages (foam cells). It has been shown that oxLDL-IC are considerably more efficient than oxLDL in induction of foam cell formation, inflammatory cytokines secretion, and cell survival promotion. Whereas oxLDL is taken up by several scavenger receptors, oxLDL-IC are predominantly internalized through the FCc receptor I (FCc RI). This study examined differences in intracellular trafficking of lipid and apolipoprotein moieties of oxLDL and oxLDL-IC and the impact on oxidative stress. Methodology/Findings: Fluorescently labeled lipid and protein moieties of oxLDL co-localized within endosomal and lysosomal compartments in U937 human monocytic cells. In contrast, the lipid moiety of oxLDL-IC was detected in the endosomal compartment, whereas its apolipoprotein moiety advanced to the lysosomal compartment. Cells treated with oxLDL-IC prior to oxLDL demonstrated co-localization of internalized lipid moieties from both oxLDL and oxLDL-IC in the endosomal compartment. This sequential treatment likely inhibited oxLDL lipid moieties from trafficking to the lysosomal compartment. In RAW 264.7 macrophages, oxLDL-IC but not oxLDL induced GFP-tagged heat shock protein 70 (HSP70) and HSP70B', which co-localized with the lipid moiety of oxLDL-IC in the endosomal compartment. This suggests that HSP70 family members might prevent the degradation of the internalized lipid moiety of oxLDL-IC by delaying its advancement to the lysosome. The data also showed that mitochondrial membrane potential was decreased and generation of reactive oxygen and nitrogen species was increased in U937 cell treated with oxLDL compared to oxLDL-IC. Conclusions/Significance: Findings suggest that lipid and apolipoprotein moieties of oxLDL-IC traffic to separate cellular compartments, and that HSP70/70B' might sequester the lipid moiety of oxLDL-IC in the endosomal compartment. This mechanism could ultimately influence macrophage function and survival. Furthermore, oxLDL-IC might regulate the intracellular trafficking of free oxLDL possibly through the induction of HSP70/70B'.

Nephrology Dialysis Transplantation, 2011

Background. Modified low-density lipoprotein (LDL) immune complexes (IC) have proinflammatory pro... more Background. Modified low-density lipoprotein (LDL) immune complexes (IC) have proinflammatory properties and play a role in albuminuria development. Methods. We measured oxidized LDL (oxLDL) and advanced glycation end-product (AGE)-LDL in IC isolated from sera of Type 1 diabetic subjects followed for 14-20 years and studied their association with abnormal albuminuria. Patients with albumin excretion rates (AER) <40 mg/24 h at baseline and follow-up (n ¼ 302) were deemed resistant to developing abnormal albuminuria. Patients with AER <40 mg/24 h at baseline whose AER levels progressed to >40 mg/24 h were considered prone to abnormal albuminuria (n ¼ 185), those who progress to AER >299 mg/24 h were considered as having macroalbuminuria (n ¼ 57). The odds of developing abnormal albuminuria were estimated by logistic regression based on natural log-transformed levels of oxLDL and AGE-LDL in IC and stratified by baseline AER decile. Results. OxLDL and AGE-LDL were significantly higher in IC isolated from patients progressing to abnormal albuminuria. In unadjusted conditional logistic analysis, an increase of 1 SD in oxLDL and AGE-LDL levels in IC significantly increased the odds ratio (OR) for development of macroalbuminuria, respectively, by a factor of 2.5 and 1.8 (P < 0.001, P ¼ 0.008). The increased odds of developing macroalbuminuria remained significant when adjusted for treatment group, diabetes duration, retinopathy, baseline hemoglobin A1c and LDL (OR ¼ 2.5 and 1.8, respectively, P < 0.01). Conclusion. Higher levels of oxLDL and AGE-LDL in circulating IC were associated with increased odds to develop abnormal albuminuria.

Journal of lipid research, 2008

Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL pla... more Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL plays an important role in limiting vascular damage by removing cholesterol and cholesteryl ester hydroperoxides from oxidized low density lipoprotein and foam cells. Methionine (Met) residues in apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, reduce peroxides in HDL lipids, forming methionine sulfoxide [Met(O)]. We examined the extent and sites of Met(O) formation in apoA-I of HDL isolated from plasma of healthy control and type 1 diabetic subjects to assess apoA-I exposure to lipid peroxides and the status of oxidative stress in the vascular compartment in diabetes. Three tryptic peptides of apoA-I contain Met residues: Q(84)-M(86)-K(88), W(108)-M(112)-R(116), and L(144)-M(148)-R(149). These peptides and their Met(O) analogs were identified and quantified by mass spectrometry. Relative to controls, Met(O) formation was significantly increased at all three locations (Met(86),...

The Journal of Clinical Endocrinology & Metabolism, 2008

Objective: We explored the relevance and significance of connective tissue growth factor (CTGF) a... more Objective: We explored the relevance and significance of connective tissue growth factor (CTGF) as a determinant of renal and vascular complications among type 1 diabetic patients.Methods and Results: We measured the circulating and urinary levels of CTGF and CTGF N fragment in 1050 subjects with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study cohort. We found that hypertensive diabetic subjects have significantly higher levels of plasma log CTGF N fragment relative to normotensive subjects (P = 0.0005). Multiple regression analysis showed a positive and independent association between CTGF N fragment levels and log albumin excretion rate (P < 0.0001). In categorical analysis, patients with macroalbuminuria had higher levels of CTGF N fragment than diabetic subjects with or without microalbuminuria (P < 0.0001). Univariate and multiple regression analyses demonstrated an independent an...

Journal of Cellular Biochemistry, 2010

Matrix metalloproteinases (MMPs) play a pivotal role in tissue remodeling and destruction in infl... more Matrix metalloproteinases (MMPs) play a pivotal role in tissue remodeling and destruction in inflammation-associated diseases such as cardiovascular disease and periodontal disease. Although it is known that interleukin (IL)-6 is a key proinflamatory cytokine, it remains unclear how IL-6 regulates MMP expression by mononuclear phagocytes. Furthermore, it remains undetermined how IL-6 in combination with hyperglycemia affects MMP expression. In the present study, we investigated the regulatory effect of IL-6 alone or in combination with high glucose on MMP-1 expression by U937 mononuclear phagocytes. We found that IL-6 is a powerful stimulator for MMP-1 expression and high glucose further augmented IL-6-stimulated MMP-1 expression. We also found that high glucose, IL-6, and lipopolysaccharide act in concert to stimulate MMP-1 expression. In the studies to elucidate underlying mechanisms, the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways were found to be required for stimulation of MMP-1 by IL-6 and high glucose. We also observed that IL-6 and high glucose stimulated the expression of c-Jun, a key subunit of AP-1 known to be essential for MMP-1 transcription. The role of c-Jun in MMP-1 expression was confirmed by the finding that suppression of c-Jun expression by RNA interference significantly inhibited MMP-1 expression. Finally, we demonstrated that similarly to U937 mononuclear phagocytes, IL-6 and high glucose also stimulated MMP-1 secretion from human primary monocytes. In conclusion, this study demonstrated that IL-6 and high glucose synergistically stimulated MMP-1 expression in mononuclear phagocytes via ERK and JNK cascades and c-Jun upregulation. Keywords Matrix metalloproteinases; Interleukin 6; Diabetes; Mitogen-activated protein kinases Interleukin-6 (IL-6) is a multifunctional cytokine involved in the acute phase response, immunity, hematopoiesis, and inflammation [Ishihara and Hirano, 2002; Kishimoto, 2006]. IL-6 plays an essential role in many chronic inflammatory diseases such as rheumatoid arthritis, systemic-onset juvenile chronic arthritis, osteoporosis, psoriasis, and autoimmune diseases such as antigen-induced arthritis and experimental allergic encephalomyelitis

Journal of Cardiovascular Pharmacology, 2011

Dipeptidyl peptidase-4 (DPP-4 or CD26) inhibitors, a new class of anti-diabetic compounds, are ef... more Dipeptidyl peptidase-4 (DPP-4 or CD26) inhibitors, a new class of anti-diabetic compounds, are effective in treatment of hyperglycemia. Since atherosclerosis-related cardiovascular diseases are the major complications of diabetes, it is important to determine the effect of DPP-4 inhibitors on atherosclerosis. In this study, nondiabetic and diabetic apolipoprotein E (apoE)-deficient mice were treated with DPP-4 inhibitor alogliptin for 24 weeks and atherosclerotic lesions in aortic origins were examined. Results showed that diabetes significantly increased atherosclerotic lesions, but alogliptin treatment reduced atherosclerotic lesions in diabetic mice. Metabolic studies showed that diabetes increased plasma glucose and alogliptin treatment reduced glucose. Furthermore, immunohistochemistry study showed that diabetes increased IL-6 and IL-1β protein expression in atherosclerotic plaques, but alogliptin treatment attenuated diabetes-augmented IL-6 and IL-1β expression. In consistence with the observations from the mouse models, our in vitro studies showed that alogliptin inhibited toll-like receptor (TLR)4-mediated upregulation of IL-6, IL-1β, and other proinflammatory cytokines by mononuclear cells. Taken together, our findings showed that alogliptin inhibited atherosclerosis in diabetic apoE-deficient mice and the actions of alogliptin on both glucose and inflammation may contribute to the inhibition.

Immunology, 2013

We reported recently that treatment of diabetic apolipoprotein E-deficient mice with the Toll-lik... more We reported recently that treatment of diabetic apolipoprotein E-deficient mice with the Toll-like receptor 4 (TLR4) antagonist Rs-LPS, a lipopolysaccharide isolated from Rhodobacter sphaeroides, inhibited atherosclerosis. Since it is known that Rs-LPS antagonizes TLR4 by targeting TLR4 co-receptor MD-2, this finding indicates that MD-2 is a potential target for the treatment of atherosclerosis. In this study, we determined if MD-2 is involved in the gene expression regulated by signalling pathways independent of TLR4. Given that interferon-c (IFNc) and hyperglycaemia play key roles in atherosclerosis, we determined if MD-2 is involved in IFN-c and high-glucose-regulated gene expression in mononuclear cells. Results showed that IFN-c and high glucose synergistically stimulated matrix metalloproteinase 1 (MMP-1), a proteinase essential for vascular tissue remodelling and atherosclerosis, in U937 mononuclear cells, but Rs-LPS inhibited the MMP-1 stimulation. To provide more evidence for a role of MD-2 in IFN-c-stimulated MMP-1, studies using antibodies and small interfering RNA demonstrated that MD-2 blockade or knockdown attenuated the effect of IFN-c on MMP-1. Furthermore, studies using PCR arrays showed that MD-2 blockade had a similar effect as IFN-c receptor blockade on the inhibition of IFN-c-stimulated pro-inflammatory molecules. Although these findings indicate the involvement of MD-2 in IFN-c signalling, we also observed that MD-2 was up-regulated by IFN-c and high glucose. We found that MD-2 up-regulation by IFN-c played an essential role in the synergistic effect of IFN-c and LPS on MMP-1 expression. Taken together, these findings indicate that MD-2 is involved in IFN-c signalling and IFN-c-augmented MMP-1 up-regulation by LPS.

Immunology, 2012

Oxidatively modified low-density lipoprotein (oxLDL) plays an important role in the development o... more Oxidatively modified low-density lipoprotein (oxLDL) plays an important role in the development of atherosclerosis. Macrophages internalize oxLDL through several membrane scavenger receptors, 1,2 and once internalized, oxLDL is transported to lysosomes for processing and degradation. 3,4 In addition, oxLDL is immunogenic and induces the generation of auto-antibodies that form circulating immune complexes (oxLDL-IC). 5,6 The uptake of oxLDL-IC by macrophages is mediated primarily through FccR1 on the cell surface and results in the release of pro-inflammatory cytokines, such as interleukin-1 b (IL-1b) and tumour necrosis factor, and the formation of lipid-laden foam cells. 7-11 We have previously shown that oxLDL-IC, as opposed to oxLDL, up-regulate the genes involved in both the inflammatory response and in cell survival. 12 Whereas oxLDL can be toxic to monocytes, it

Diabetic Medicine, 2006

Aims To relate nuclear magnetic resonance lipoprotein subclass profiles (NMR-LSP) and other lipop... more Aims To relate nuclear magnetic resonance lipoprotein subclass profiles (NMR-LSP) and other lipoprotein-related factors with carotid intima-media thickness (IMT) in Type 1 diabetes. Methods Lipoprotein-related factors were determined in sera (obtained in 1997-1999) from 428 female [age 39 ± 7 years (mean ± SD)] and 540 male (age 40 ± 7 years) Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) participants. NMR quantifies chylomicrons, three very low-density lipoprotein (VLDL) subclasses, intermediate density lipoprotein (IDL), three low-density lipoprotein (LDL) subclasses, two high-density lipoprotein (HDL) subclasses, mean VLDL, LDL and HDL size, and LDL particle concentration. Conventional lipids, ApoA1, ApoB and Lp(a) and in vitro LDL oxidizibility were also measured. IMT was determined (in 1994-1995) using high-resolution B-mode ultrasound. Relationships between IMT and lipoproteins were analysed by multiple linear regression, controlling for age, diabetes-related factors, and cardiovascular disease (CVD) risk factors. Results IMT associations with lipoproteins were stronger for the internal than the common carotid artery, predominantly involving LDL. Internal carotid IMT was positively (P < 0.05) associated with NMR-based LDL subclasses and particle concentration, and with conventional LDL-cholesterol and ApoB in both genders. Common carotid IMT was associated, in men only, with large VLDL, IDL, conventional LDL cholesterol and ApoB. Conclusions NMR-LSP reveals significant associations with carotid IMT in Type 1 diabetic patients, even 4 years after IMT measurement. NMR-LSP may aid early identification of high-risk diabetic patients and facilitate monitoring of interventions. Longer DCCT/EDIC cohort follow-up will yield CVD events and IMT progression, permitting more accurate assessment of pre-morbid lipoprotein profiles as determinants of cardiovascular risk in Type 1 diabetes.