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Aims The aim of this work was to evaluate the effects of treatment of hypertension on the autoantibodies to apolipoprotein B-derived peptides (anti-ApoB-D peptide Abs) response, inflammation markers and vascular function. Main methods Eighty-eight patients with hypertension (stage 1 or 2) were recruited and advised to receive perindopril (4 mg), hydrochlorothiazide (25 mg), or indapamide (1.5 mg) for 12 weeks in a blinded fashion. Office and 24-h ambulatory blood pressure monitoring (24 h ABPM), flow-mediated dilatation (FMD), nitrate-induced dilatation (NID), titers of IgG and IgM anti-ApoB-D peptide Abs, hsCRP, and interleukins (IL-8 and IL-10) were evaluated at baseline and 12 weeks after therapies. Key findings All treatments reduced office BP, and improved FMD ( P vs . baseline). The NID was improved only in the perindopril arm ( P vs . baseline). The 24 h-ABPM was reduced with perindopril and hydrochlorothiazide therapies ( P vs . baseline), but not with indapamide, and this effect was followed by increase in titers of IgM Anti-ApoB-D peptide Abs ( P vs . baseline), without modifications in titers IgG Anti-ApoB-D peptide Abs and interleukins. Multivariable regression analysis has shown that change in the titers of IgM anti-ApoB-D peptide was associated with the changes in FMD (β − 0.347; P Significance These findings shed light to a possible modulator effect of the antihypertensive therapy on the natural immunity responses and vascular function.

Aims To compare the effects of two of the most effective lipid-lowering therapies with similar LDL-cholesterol reduction capacity on the innate and adaptive immune responses through the evaluation of autoantibodies anti-oxidized LDL (anti-oxLDL Abs) and electronegative LDL [LDL(−)] levels. Main methods We performed a prospective, randomized, open label study, with parallel arms and blinded endpoints. One hundred and twelve subjects completed the study protocol and received rosuvastatin 40 mg or ezetimibe/simvastatin 10/40 mg for 12 weeks. Lipids, apolipoproteins, LDL(−), and anti-oxLDL Abs (IgG) were assayed at baseline and end of study. Key findings Main clinical and laboratory characteristics were comparable at baseline. Lipid modifications were similar in both treatment arms, however, a significant raise in anti-oxLDL Abs levels was observed in subjects treated with rosuvastatin (p = 0.026 vs. baseline), but not in those receiving simvastatin/ezetimibe. (p = 0.233 vs. baseline), thus suggesting modulation of adaptive immunity by a potent statin. Titers of LDL(−) were not modified by the treatments. Significance Considering atherosclerosis as an immune disease, this study adds new information, showing that under similar LDL-cholesterol reduction, the choice of lipid-lowering therapy can differently modulate adaptive immune responses.

Low Plasma Titer Of Autoantibodies Against Degraded Apob100 Is Independently Associated With Myocardial Infarction

Neodymium based fluorescence presents several advantages in comparison to conventional rare earth or enzyme–substrate based fluorescence emitting sources (e.g.Tb, HRP) . Based on this fact we have herein explored a Nd-based fluoroimmunoassay. We efficiently detected the presence of an oxidized low-density lipoprotein (oxLDL) in human plasma a well-known marker for cardiovascular diseases, which causes around 30% of deaths worldwide. Conventional fluoroimmunoassay uses time-resolved luminescence techniques, with detection in the visible range, to eliminate the fluorescence background from the biological specimens. By using an immunoassay based on functionalized Y 2 O 3 :Nd 3+ nanoparticles, where the excitation and emission processes in the Nd 3+ ion occur in the near-infrared (NIR) region, we have succeeded in eliminating the interferences from the biological fluorescence background, avoiding the use of time-resolved techniques. This yields higher emission intensity from the Nd 3+ -nanolabels and efficient detection of anti-oxidized low-density lipoproteins (anti-oxLDL) by Y 2 O 3 :Nd 3+ -antibody–antigen conjugation, leading to a novel biolabeling method.

OBJECTIVES: To investigate whether oxidized low-density lipoprotein is a suitable predictor of peripheral arterial disease severity. The role of oxidized low-density lipoprotein in the pathogenesis of atherosclerosis has already been investigated. Its relevance as a predictor of the appearance and worsening of coronary arterial disease is also well known. However, the same is not true regarding peripheral arterial disease. METHOD: Eighty-five consecutive patients with an ankle-brachial pressure index (ABPI) < 0.9 and the presence of either intermittent claudication or critical lower leg ischemia were included. The plasma level of IgG autoantibodies against oxidized low-density lipoprotein was evaluated through an enzyme-linked immunosorbent assay. The results were categorized into quartiles according to the ankle-brachial pressure index (a marker of peripheral arterial disease severity), and significant differences were investigated with the Kruskal-Wallis test. RESULTS: There was no significant difference between the quartiles for this population (p = 0.33). No correlation was found between the ankle-brachial pressure index and oxidized low-density lipoprotein levels in subjects with clinically evident peripheral arterial disease with a wide range of clinical manifestations. CONCLUSIONS: Oxidized low-density lipoprotein is not a good predictor of peripheral arterial disease severity.

We analyzed the impact of chronic exposure to urban air pollution on the development of atherosclerosis. Hyperlipemic mice (LDLR −/− ) were submitted to a high fat diet and air pollution for four months. We measured the susceptibility of LDL to oxidative modifications (TBARS), the presence of anti-oxLDL and an apoB-derived peptide (apoB-D) in blood and the degree of atherosclerosis in the aortic arch. Air pollution increased the susceptibility of LDL to oxidation as well as anti-oxLDL and anti-apo-B levels. These levels were even higher than in mice submitted to a high fat diet and non-polluted air. The lipid content of the atherosclerotic plaques in the aorta was increased in groups with a high cholesterol diet independently of the air quality. However, the thickness of the arterial wall was greater in mice fed a high lipid diet with polluted air. Thus, we conclude that urban air pollution exacerbates the susceptibility of LDL to oxidation, atherogenesis and vascular remodeling in hyperlipemic mice and that an immune response accompanies this process.

Monocytes/macrophages and lymphocytes have a key role in the pathogenesis of atherosclerosis through the production of inflammatory and anti-inflammatory cytokines. We evaluated mRNA expression and protein production of CCL2, CXCL8, CXCL9, CXCL10, IFN-gamma and IL-10 in vitro as well as the expression of the CCR2 and CXCR3 receptors in peripheral blood mononuclear cells (PBMCs) of patients with coronary artery disease (CAD) and healthy controls in the presence or absence of oxidized LDL (oxLDL). Patients with CAD showed higher constitutive expression of CCL2, CXCL8, CXCL9, CXCL10 and IFN-gamma mRNA and, after stimulation with oxLDL, higher expression of CCL2 and CXCL8 mRNA than the control group. We also detected higher levels of CCL2 and CXCL8 in supernatants of oxLDL-stimulated PBMCs from CAD patients than in corresponding supernatants from controls. Patients with CAD had a higher percentage of constitutive CCR2(+) and CXCR3(+) cells after stimulation with oxLDL. Among CAD patients, the main differences between the stable (SA) and unstable angina (UA) groups were lower IL-10 mRNA production in the latter group. Altogether, our data suggest that PBMCs from CAD patients are able to produce higher concentrations of chemokines and cytokines involved in the regulation of monocyte and lymphocyte migration and retention in atherosclerotic lesions.

In this work, we investigated the impact of testosterone deficiency and cholesteryl ester transfer protein (CETP) expression on lipoprotein metabolism and diet-induced atherosclerosis. CETP transgenic mice and nontransgenic (nTg) littermates were studied 4 weeks after bilateral orchidectomy or sham operation. Castrated mice had an increase in the LDL fraction (+36% for CETP and +79% for nTg mice), whereas the HDL fraction was reduced (−30% for CETP and −11% for nTg mice). Castrated mice presented 1.7-fold higher titers of anti-oxidized LDL (Ox-LDL) antibodies than sham-operated controls. Plasma levels of CETP, lipoprotein lipase, and hepatic lipase were not changed by castration. Kinetic studies showed no differences in VLDL secretion rate, VLDL-LDL conversion rate, or number of LDL and HDL receptors. Competition experiments showed lower affinity of LDL from castrated mice for tissue receptors. Diet-induced atherosclerosis studies showed that testosterone deficiency increased by 100%, and CETP expression reduced by 44%, the size of aortic lesion area in castrated mice. In summary, testosterone deficiency increased plasma levels of apolipoprotein B-containing lipoproteins (apoB-LPs) and anti-OxLDL antibodies, decreased LDL receptor affinity, and doubled the size of diet-induced atherosclerotic lesions. The expression of CETP led to a milder increase of apoB-LPs and reduced atherosclerotic lesion size in testosterone-deficient mice.

Auto antigens such as oxidized LDL have been implicated as atherogenic agents found in atheromatous lesions. It has not been observed whether percutaneous coronary intervention (PCI) can modulate the natural or adaptive humoral immune response to auto antigens according to the degree of

The incidence of atherosclerosis can be modified by diet, and plant-derived proteins have a beneficial effect, but the underlying mechanisms remain unclear. It has been suggested that oxidized LDL (oxLDL) and autoantibodies against oxLDL are important in the development of atherosclerosis. We analyzed these factors in rabbits fed a nonpurified diet supplemented with high cholesterol (10.0 g/kg) containing either 270.0 g/kg casein (CAS, n = 10) or 270.0 g/kg soy protein isolate (SPI, n = 10) for 2 mo. Plasma and purified serum LDL from rabbits were analyzed at d 0, 15, 30, 45 and 60 of treatment, and the size of atherosclerotic lesions was evaluated at d 60 of treatment. CAS-fed rabbits had significantly higher plasma cholesterol at d 15-45 and LDL cholesterol levels at d 15 and 30. Levels of trilinolein and phosphatidylcholine hydroperoxides were higher in the LDL fraction of rabbits fed CAS than in those fed SPI. Also, CAS-fed rabbits had higher levels of highly oxidized LDL [monoclonal antibody (mAb) 24-reactive oxLDL] in plasma at d 60, whereas SPI-fed rabbits had higher levels of minimally oxidized LDL (mAb 28-reactive oxLDL) at d 45. These results were consistent with the earlier formation of anti-oxLDL antibodies and the presence of a larger area of atherosclerotic lesion in rabbits fed the CAS diet. These data indicate the importance of both the type of dietary protein used in the induction of atherosclerosis and the relevance of immunologic mechanisms in addition to biochemical and physiologic factors in the pathogenesis of atherosclerosis.

The ability of a T helper (Th) epitope to induce help for B cells recognizing different determinants within a multideterminant antigen was investigated. Chimeric fusion proteins, containing inserts of single or multiple copies of the Th epitope ovalbumin 323-339 (ova) at two different positions, were compared with respect to their ability to induce specific antibody production and ova-specific T cell activation. The antibody responses against B cell determinants at the amino and carboxy terminus, respectively was differently influenced by the molecular positioning of the inserted Th determinant. All ova-containing fusion proteins induced antibody production against the B cell determinant at the amino terminal end irrespective of the positioning of ova. In addition, multiple copies of ova in any position led to increased levels of antibody production against this epitope. In contrast, T cell help for antibody production against the determinant at the carboxy terminus was more effective after insertion of multiple copies of ova in a distal than in an adjacent position. Furthermore a fusion protein, containing four copies of ova effectively elicited T cell help for high levels of antibody production against both examined B cell determinants, showing that activated Th cells recognizing a single epitope could simultaneously provide help for distinct sets of B cells specific for widely separated epitopes within a protein. Immunodominant T cell recognition of ova in all chimeric peptides, independently of its position, was demonstrated by lymph node cell (LNC) proliferation of primed BALB/c mice. The level of ova-specific T cell proliferation was similar, irrespective of which chimeric peptide that had been used for priming, and thus did not reveal any differences in T cell priming efficiencies related to the number of ova copies in the fusion proteins. However, when the peptides were presented to a ova-specific T cell line by A20 B lymphoma cells, a close correlation between IL-2 production by the clonal T cells and the number of ova epitopes in the chimeric peptides was observed. Thus, increased cytokine production by ova-specific T cells may be important for the increased level of in vivo antibody production observed in response to multiple copies of ova in the chimeric antigens.

The present report describes the mitogenic effect of recombinant IGF-2 on cultured human keratinocytes and fibroblasts compared to that of IGF-1. Furthermore, the modulating effect of a recently expressed recombinant form of placental-derived IGF-binding protein 1 (IGFBP-1) on IGF-induced proliferation was examined. A dose-dependent increase, up to 100%, in cell proliferation was seen in cultured human keratinocytes with IGF-2 and -1 and the proliferative response was comparable to the effect of epidermal growth factor (EGF). In human fibroblasts, IGF-1 stimulated DNA synthesis up to 300% for IGF-1 and up to 200% for IGF-2. The mitogenic effect of IGF-1 was enhanced by IGFBP-1 in both cell types. In contrast, the IGF-2-induced mitogenic effect was unperturbed. These findings indicate that the interaction between IGFs and their binding proteins may induce different responses depending upon the ligand and the target cell.