HSP90 expression is associated with features of plaque instability in advanced human lesions. HSP90 inhibitors reduce inflammatory responses in atherosclerosis, suggesting that HSP90 could be a novel therapeutic target in atherosclerosis.
Objective-In the search of novel biomarkers of abdominal aortic aneurysm (AAA) progression, proteins released by intraluminal thrombus (ILT) were analyzed by a differential proteomic approach. Methods and Results-Different layers (luminal/abluminal) of the ILT of AAA were incubated, and the proteins released were analyzed by 2-dimensional difference in-gel electrophoresis. Several differentially expressed proteins involved in main AAA pathological mechanisms (proteolysis, oxidative stress, and thrombosis) were identified by mass spectrometry. Among the proteins identified, peroxiredoxin-1 (PRX-1) was more released by the luminal layer compared with the abluminal layer of the ILT, which was further validated by Western blot, ELISA, and immunohistochemistry. We demonstrated increased PRX-1 serum levels in AAA patients compared with healthy subjects and also positive correlation among PRX-1 and AAA diameter, plasmin-antiplasmin, and myeloperoxidase levels. Finally, a prospective study revealed a positive correlation between PRX-1 serum levels and AAA expansion rate. Moreover, the combination of PRX-1 and AAA size had significantly additive value in predicting growth. is an important health problem, which occurs in up to 9% of adults older than 65 years of age. The incidence of asymptomatic and ruptured AAA has increased during recent decades, causing Ϸ1% to 2% of male deaths in Western countries. 1 Because AAAs are usually asymptomatic before rupture, the present clinical challenges are to diagnose AAA at an early stage and to decipher the biological mechanisms leading to progressive dilatation and finally rupture, to develop new diagnostic and therapeutic approaches. Identification of biomarkers could help to target both objectives. Conclusion-SeveralPrevious studies have identified AAA biomarkers by studying the levels of different molecules potentially related to AAA pathological mechanisms. 2,3 A different noncandidate biomarker strategy using a set of modern high-throughput technologies, including proteomics, will offer new opportunities to gain a deeper insight into disease processes, including their molecular mechanisms, the risk factors involved, and the analysis of disease progression. 4,5 We have previously reported a differential proteomic approach to identify new atherothrombosis biomarkers released by the arterial wall into plasma using normal and pathological arteries in culture. 6,7 The presence of an intraluminal thrombus (ILT) is a main feature of AAA, and recent data suggest that the biological activities of ILT play a major role in AAA development in humans. 8 In this study, different layers (luminal/abluminal) from the ILT of human AAA patients were incubated in protein-free medium, and the released proteins were analyzed by a gel-based (2-dimensional difference in-gel electrophoresis [2D-DIGE]) proteomic approach followed by protein identification by mass spectrometry (MS). We focused on peroxiredoxin-1 (PRX-1) in view of its potential role in modulating oxidative stress and thus validated its ...
Objective-Polymorphonuclear neutrophils (PMNs) play a main role in abdominal aortic aneurysm (AAA) progression.We have analyzed circulating PMNs isolated from AAA patients and controls by a proteomic approach to identify proteins potentially involved in AAA pathogenesis. Methods and Results-PMNs from 8 AAA patients (4 large AAA Ͼ5 cm and 4 small AAA 3-5 cm) and 4 controls were analyzed by 2D differential in-gel electrophoresis. Among differentially expressed spots, several proteins involved in redox balance were identified by mass spectrometry (eg, cyclophilin, thioredoxin reductase, catalase). Diminished catalase expression and activity were observed in PMNs from AAA patients compared with controls. In contrast, PMNs from AAA patients displayed higher H 2 O 2 and myeloperoxidase levels than PMNs from controls. Moreover, a significant decrease in catalase mRNA levels was observed in PMNs after phorbol 12-myristate 13-acetate incubation. Catalase plasma levels were also decreased in large (nϭ47) and small (nϭ56) AAA patients compared with controls (nϭ34). We observed catalase expression in AAA thrombus and thrombus-conditioned medium, associated with PMN infiltration. Furthermore, increased H 2 O 2 levels were observed in AAA thrombus-conditioned medium compared with the media layer. Key Words: aneurysms Ⅲ antioxidants Ⅲ leukocytes A bdominal aortic aneurysm (AAA) is an important health problem in elderly. In cross-sectional studies, the prevalence varies from 3% to 8%. 1 In elderly men, AAAs may cause as much as 2% to 3% of all deaths. 1 Because AAAs are usually asymptomatic, the present clinical challenges are early diagnosis and deciphering the biological mechanisms responsible for the progressive dilatation and final rupture to develop new diagnostic and therapeutic approaches. Conclusion-DiminishedAlthough polymorphonuclear neutrophils (PMNs) represent the major class of leukocytes, they have received little attention in atherothrombosis. 2,3 However, recent evidence is revealing a previously unappreciated role of PMN in experimental 4,5 and human 6,7 AAAs. PMNs can contribute to main mechanisms of AAA evolution, namely intraluminal thrombus (ILT) formation, oxidative stress, proteolytic degradation of the aortic media, and adventitial inflammation. 8 AAAs are characterized by the presence of a mural ILT-containing platelets, red blood cells (RBCs), and PMNs, particularly abundant within the luminal layer of human thrombus. 6 -8 AAAs are also characterized by destructive connective tissue remodeling, including depletion of aortic elastin and fragmentation of medial elastic fibers. 9 Finally, inflammatory cells (macrophages and neutrophils) are also evident within the adventitia of human AAAs. 10 Interestingly, PMNs depletion is able to inhibit experimental AAA formation. 11 More recently, short-term preoperative doxycycline therapy improved the proteolytic balance in human AAA, presumably via an effect on aortic wall neutrophil content. 12 These data highlight the potential interest of analyzing the PMNs p...
Syncytin‐1 is the envelope protein of the human endogenous retrovirus W (HERV‐W). It has been related to multiple sclerosis (MS) but its role in cellular immunity and its pathogenic mechanism in the autoimmune context are not fully understood. We analyzed syncytin‐1 levels in peripheral blood mononuclear cells (PBMC) subsets from healthy donors, MS patients in relapse or remission, and patients with acute infections by flow cytometry. PBMC cultures were also prepared to analyze protein expression kinetics. MS patients had higher levels of syncytin‐1 levels than controls. We found that syncytin‐1 is elevated in monocytes during MS relapses and infections. Cells expressing syncytin‐1, including monocytes, T and B lymphocytes, and NKs presented mainly an activated phenotype and, upon stimulation with LPS, its levels increased rapidly on antigen‐presenting cells. Syncytin‐1 ligation promoted the activation of monocytes, as demonstrated by the upregulation of CD80 and the nonclassical subset CD14low CD16+. Our results suggest an important role for syncytin‐1 in the activation of leukocytes. Given that the expression of syncytin‐1 is upregulated in MS patients, this protein might be contributing to the autoimmune cascade in the disease.
Abdominal aortic aneurysm (AAA) is an important health problem, both because of AAA rupture and death and because of increased cardiovascular mortality. Identification of new biomarkers of AAA may suggest novel pathological mechanisms and targets for new medical treatments to slow AAA progression. Metabolic changes in AAA patients were mainly related to carbohydrate and lipid metabolism and many of these changes can be associated with a situation of insulin resistance (which can be related to metabolic syndrome) together with altered amino acid metabolism. For the first time, metabolites that can be associated with differential metabolism by the gut microflora of AAA patients have also been found. Moreover, aminomalonic acid in plasma has been shown to be the metabolite with the biggest difference between patients suffering from large aneurysm (>5 cm) and controls.
Several variants in strong linkage disequilibrium (LD) at the SP140 locus have been associated with multiple sclerosis (MS), Crohn's disease (CD) and chronic lymphocytic leukemia (CLL). To determine the causal polymorphism, we have integrated high-density data sets of expression quantitative trait loci (eQTL), using GEUVADIS RNA sequences and 1000 Genomes genotypes, with MS-risk variants of the high-density Immunochip array performed by the International Multiple Sclerosis Genetic Consortium (IMSGC). The variants most associated with MS were also correlated with a decreased expression of the full-length RNA isoform of SP140 and an increase of an isoform lacking exon 7. By exon splicing assay, we have demonstrated that the rs28445040 variant was the causal factor for skipping of exon 7. Western blots of peripheral blood mononuclear cells from MS patients showed a significant allele-dependent reduction of the SP140 protein expression. To confirm the association of this functional variant with MS and to compare it with the best-associated variant previously reported by GWAS (rs10201872), a case-control study including 4384 MS patients and 3197 controls was performed. Both variants, in strong LD (r(2) = 0.93), were found similarly associated with MS [P-values, odds ratios: 1.9E-9, OR = 1.35 (1.22-1.49) and 4.9E-10, OR = 1.37 (1.24-1.51), respectively]. In conclusion, our data uncover the causal variant for the SP140 locus and the molecular mechanism associated with MS risk. In addition, this study and others previously reported strongly suggest that this functional variant may be shared with other immune-mediated diseases as CD and CLL.
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