Circulating microparticles and endothelial progenitor cells in atherosclerosis; pharmacological effects of irbesartan.
J Thromb Haemost. 2012 Feb 3;
Authors: Georgescu A, Alexandru N, Andrei E, Titorencu I, Dragan E, Tarziu C, Ghiorghe S, Badila E, Bartos D, Popov D
Abstract
Aims: This study aimed to (a) employ our newly designed model, the hypertensive-hypercholesterolemic hamster (HH) in order to find whether a correlation exist between circulating microparticles (MPs), endothelial progenitor cells (EPCs) and their contribution to vascular dysfunction and (b) to assess the effect of irbesartan treatment on HH animals (HHI). Methods and Results: The results showed that compared to control (C) group, HH displayed: (i) a significantly increase in plasma cholesterol and triglyceride concentration, and an augmentation of systolic and diastolic arterial blood pressure, and of heart rate; (ii) a marked elevation of MPs and a significant decrease in EPCs; (iii) structural modifications of arterial wall correlated with altered protein expression of MMP2, MMP9, MMP12, TIMP1, TIMP2 and collagen type I and III; (iv) a considerably altered reactivity of arterial wall closely correlated with MPs and EPC adherence; (v) an inflammatory process characterised by augmented expression of P-Selectin, E-Selectin, vWF, TF, IL-6, MCP-1, RANTES. Additionally, the experiments showed the potential of irbesartan to correct all altered parameters in HH and to mobilize EPCs by NO, chemokines and adhesion molecules dependent mechanism. Conclusions: Hypertension associated with hypercholesterolemia is accompanied by structural modifications and expression of pro-inflammatory molecules by vessel wall, the alteration of vascular tone, enhanced release of MPs and reduced EPCs; the ratio between the latter two may be considered as a marker of vascular dysfunction. Irbesartan that exhibit a pharmacological control on the levels of MPs and EPCs has the potential to restore homeostasis of the arterial wall.
PMID: 22303879 [PubMed - as supplied by publisher]
Intravascular Optical Coherence Tomography Detection of Atherosclerosis and Inflammation in Murine Aorta.
Arterioscler Thromb Vasc Biol. 2012 Feb 2;
Authors: Tahara S, Morooka T, Wang Z, Bezerra HG, Rollins AM, Simon DI, Costa MA
Abstract
OBJECTIVE: The goal of this study was to evaluate the feasibility of imaging the aorta of apolipoprotein E-deficient (ApoE(-/-)) mice for the detection of atherosclerosis and macrophages using optical coherence tomography (OCT) compared with histology. METHODS AND RESULTS: Atherosclerosis was induced by high-fat diet in 7-week-old ApoE(-/-) mice for 10 (n=7) and 22 (n=7) weeks. Nine-week-old ApoE(-/-) mice (n=7) fed a standard chow diet were used as controls. OCT images of a 10-mm descending aorta in situ were performed in 4 mice for each, and plaque and macrophages were determined at 0.5-mm intervals. Automated detection and quantification of macrophages were performed independently using a customized algorithm. Coregistered histological cross-sections were stained with hematoxylin-eosin, Mac-3, and von Kossa. Three mice in each group had en face OCT imaging to detect macrophages, which were compared with lipid-positive area with Sudan IV. OCT images were successfully acquired in all mice. OCT and histology were able to discriminate macrophages and plaque among the 3 groups and showed excellent correlation for (1) visual detection of plaque (r=0.98) and macrophages (r=0.93), (2) automated detection and quantification of macrophages by OCT versus Mac-3-positive area (r=0.92), and (3) en face OCT detection of macrophages versus Sudan IV-positive area (r=0.92). CONCLUSIONS: Murine intraaortic OCT is feasible and shows excellent correlation with histology for detection of atherosclerotic plaque and macrophages.
PMID: 22308042 [PubMed - as supplied by publisher]
Absence of Acute Inhibitory Effect of Insulin on Chylomicron Production in Type 2 Diabetes.
Arterioscler Thromb Vasc Biol. 2012 Feb 2;
Authors: Nogueira JP, Maraninchi M, Béliard S, Padilla N, Duvillard L, Mancini J, Nicolay A, Xiao C, Vialettes B, Lewis GF, Valéro R
Abstract
OBJECTIVE: Overproduction of intestinally derived apoB-48-containing triglyceride-rich lipoproteins (TRLs) (chylomicrons) has recently been described in type 2 diabetes, as is known for hepatic TRL-apoB-100 (very-low-density lipoprotein) production. Furthermore, insulin acutely inhibits both intestinal and hepatic TRL production, whereas this acute inhibitory effect on very-low-density lipoprotein production is blunted in type 2 diabetes. It is not currently known whether this acute effect on chylomicron production is similarly blunted in humans with type 2 diabetes. METHODS AND RESULTS: We investigated the effect of acute hyperinsulinemia on TRL metabolism in 18 type 2 diabetic men using stable isotope methodology. Each subject underwent 1 control (saline infusion [SAL]) lipoprotein turnover study followed by a second study, under 1 of the 3 following clamp conditions: (1) hyperinsulinemic-euglycemic, (2) hyperinsulinemic-hyperglycemic, or (3) hyperinsulinemic-euglycemic plus intralipid and heparin. TRL-apoB-48 and TRL-apoB-100 production and clearance rates were not different between SAL and clamp and between the different clamp conditions, except for significantly lower TRL-apoB-100 clearance and production rates in hyperinsulinemic-euglycemic plus intralipid and heparin clamp compared with SAL. CONCLUSIONS: This is the first demonstration in individuals with type 2 diabetes that chylomicron production is resistant to the normal acute suppressive effect of insulin. This phenomenon may contribute to the highly prevalent dyslipidemia of type 2 diabetes and potentially to atherosclerosis.Clinical Trial Registration-URL: www.clinicaltrials.gov. Unique identifier: NCT00950209.
PMID: 22308041 [PubMed - as supplied by publisher]
In Vivo Targeting of Inflammation-Associated Myeloid-Related Protein 8/14 Via Gadolinium Immunonanoparticles.
Arterioscler Thromb Vasc Biol. 2012 Feb 2;
Authors: Maiseyeu A, Badgeley MA, Kampfrath T, Mihai G, Deiuliis JA, Liu C, Sun Q, Parthasarathy S, Simon DI, Croce K, Rajagopalan S
Abstract
OBJECTIVE: Myeloid-related protein (Mrp) 8/14 complex (is a highly expressed extra cellularly secreted protein, implicated in atherosclerosis. In this study, we evaluated the feasibility of targeting Mrp in vivo through synthetic immuno-nanoprobes. METHODS AND RESULTS: Anti-Mrp-14 and nonspecific IgG-conjugated gadolinium nanoprobes (aMrp-) were synthesized and characterized. Pharmacokinetics and vascular targeting via MRI of the formulations were assessed in vivo in high fat-fed apolipoprotein E deficient (ApoE(-/-)), ApoE(-/-)/Mrp14(-/-) (double knockout) and chow-fed wild-type (C57BL/6) mice were. Bone marrow-derived myeloid progenitor cells were isolated from both ApoE(-/-) and double knockout mice and differentiated to macrophages and were treated with LPS, with or without Mrp8, Mrp14, or Mrp8/14, and conditioned media was collected and used for in vitro studies. Mrp-activated cells secreted significant amounts of proinflammatory cytokines, which were abolished by pretreatment with aMrp-NP. We show in vitro that aMrp-NP binds endothelial cells previously treated with conditioned media containing Mrp8/14. MRI following intravenous delivery of aMrp-NP revealed prolonged and substantial delineation of plaque in ApoE(-/-) but not double knockout or wild-type animals. Nonspecific IgG-conjugated gadolinium nanoprobe-injected animals in all groups did not show vessel wall enhancement. Flow-cytometric analysis of aortic digesta revealed aMrp-NP presence in Ly-6G(+), CD11b(+), CD11c(+), and CD31(+) cells in ApoE(-/-) but not in double knockout animals. CONCLUSIONS: Targeted imaging with aMrp-NP demonstrates enhancement of plaque with binding to inflammatory cells and reduction in inflammation. This strategy has promise as a theranostic approach for atherosclerosis.
PMID: 22308043 [PubMed - as supplied by publisher]
Sphingosine-1-Phosphate Receptor 3 Promotes Neointimal Hyperplasia in Mouse Iliac-Femoral Arteries.
Arterioscler Thromb Vasc Biol. 2012 Feb 2;
Authors: Shimizu T, De Wispelaere A, Winkler M, D’Souza T, Caylor J, Chen L, Dastvan F, Deou J, Cho A, Larena-Avellaneda A, Reidy M, Daum G
Abstract
OBJECTIVE: The objective of this study was to define a role for sphingosine-1-phosphate receptor 3 (S1PR3) in intimal hyperplasia. METHODS AND RESULTS: A denudation model of the iliac-femoral artery in wild-type and S1PR3-null mice was used to define a role for S1PR3 in the arterial injury response because we found in humans and mice that expression of S1PR3 was higher in these arteries compared with carotid arteries. At 28 days after surgery, wild-type arteries formed significantly larger lesions than S1PR3-null arteries.T Bromodeoxyuridine labeling experiments demonstrated that on injury, wild-type arteries exhibited higher medial as well as intimal proliferation than S1PR3-null arteries. Because S1PR3 expression in vitro was low, we expressed S1PR3 in S1PR3-null smooth muscle cells (SMCs) using retroviral-mediated gene transfer to study the effects of S1PR3 on cell functions and signaling. SMCs expressing S1PR3, but not vector-transfected controls, responded to sphingosine-1-phosphate stimulation with activation of Rac, Erk, and Akt. SMCs expressing S1PR3 also migrated more. CONCLUSIONS: In humans and mice, S1PR3 expression was higher in iliac-femoral arteries compared with carotid arteries. S1PR3 promoted neointimal hyperplasia on denudation of iliac-femoral arteries in mice, likely by stimulating cell migration and proliferation through activation of signaling pathways involving Erk, Akt, and Rac.
PMID: 22308044 [PubMed - as supplied by publisher]
Dysregulation of global microRNA expression in splenic marginal zone lymphoma and influence of chronic hepatitis C virus infection.
Leukemia. 2012 Feb 6;
Authors: Peveling-Oberhag J, Crisman G, Schmidt A, Döring C, Lucioni M, Arcaini L, Rattotti S, Hartmann S, Piiper A, Hofmann WP, Paulli M, Küppers R, Zeuzem S, Hansmann ML
Abstract
The precise molecular pathogenesis of splenic marginal zone lymphoma (SMZL) is still unknown. Clinical and epidemiologic data suggest that chronic hepatitis C virus (HCV) infection may play an etiological role in a subset of cases. We performed a large-scale miRNA expression profiling analysis of 381 miRNAs by quantitative reverse-transcription PCR (Q-RT-PCR) of 26 microdissected splenic tissue samples (7 HCV(+) SMZL; 8 HCV(-) SMZL and 11 non-neoplastic splenic controls). Single assay Q-RT-PCR and miRNA in situ hybridisation were used to confirm the results in an independent cohort. Unsupervised hierarchical clustering of miRNA expression profiles demonstrated a distinct signature of SMZL compared to the normal splenic marginal zone. Supervised analysis revealed differentially expressed miRNAs, including miRNAs with previously recognized tumor suppressive or oncogenic potential. Five miRNAs were found significantly overexpressed in SMZL, including miR-21, miR-155, and miR-146a, while seven miRNAs showed significantly reduced expression, including miR-139, miR-345, miR-125a, and miR-126. Furthermore, we identified miR-26b, a miRNA known to have tumor suppressive properties, as significantly downregulated in SMZL arising in HCV positive patients (P=0.0016). In conclusion, there is a characteristic dysregulation of miRNA expression in SMZL with a possible implication in its molecular tumorigenesis.Leukemia accepted article preview online, 6 February 2012; doi:10.1038/leu.2012.29.
PMID: 22307176 [PubMed - as supplied by publisher]
Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European leukemianet working group.
Leukemia. 2012 Feb 6;
Authors: Westers TM, Ireland R, Kern W, Alhan C, Balleisen JS, Bettelheim P, Burbury K, Cullen M, Cutler JA, Della Porta MG, Dräger AM, Feuillard J, Font P, Germing U, Haase D, Johansson U, Kordasti S, Loken MR, Malcovati L, Te Marvelde JG, Matarraz S, Milne T, Moshaver B, Mufti GJ, Ogata K, Orfao A, Porwit A, Psarra K, Richards SJ, Subirá D, Tindell V, Vallespi T, Valent P, van der Velden VH, de Witte TM, Wells DA, Zettl F, Béné MC, van de Loosdrecht AA
Abstract
Flow cytometry (FC) is increasingly recognized as an important tool in the diagnosis and prognosis of myelodysplastic syndromes (MDS). However, validation of current assays and agreement upon the techniques are prerequisites for its widespread acceptance and application in clinical practice. Therefore, a working group was initiated (Amsterdam, 2008) to discuss and propose standards for FC in MDS. In 2009 and 2010, representatives from 23, mainly European, institutes participated in the 2nd and 3rd European LeukemiaNet (ELN) MDS workshops. In the present report, minimal requirements to analyze dysplasia are refined. The proposed core markers should enable a categorization of FC results in cytopenic patients as “normal”, “suggestive of” or “diagnostic of” MDS. A FC report should include a description of validated FC abnormalities such as aberrant marker expression on myeloid progenitors and, furthermore, dysgranulopoiesis and/or dysmonocytopoiesis if at least two abnormalities are evidenced. The working group is dedicated to initiate further studies to establish robust diagnostic and prognostic FC panels in MDS. An ultimate goal is to refine and improve diagnosis and prognostic scoring systems. Finally, the working group stresses that FC should be part of an integrated diagnosis, rather than a separate technique.Leukemia accepted article preview online, 6 February 2012; doi:10.1038/leu.2012.30.
PMID: 22307178 [PubMed - as supplied by publisher]
Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia.
Leukemia. 2012 Feb 6;
Authors: Vilas-Zornoza A, Agirre X, Abizanda G, Moreno C, Segura V, De Martino Rodriguez A, José-Eneriz ES, Miranda E, Martín-Subero JI, Garate L, Blanco-Prieto MJ, Jalón JG, Rio P, Rifón J, Cigudosa JC, Martinez-Climent JA, Román-Gómez J, Calasanz MJ, Ribera JM, Prósper F
Abstract
Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous (i.v.) administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving Vincristine and Dexametasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with Vincristine and Dexametasone. Our results demonstrate the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.Leukemia accepted article preview online, 6 February 2012; doi:10.1038/leu.2012.31.
PMID: 22307227 [PubMed - as supplied by publisher]
Consequences of heat shock protein 72 (Hsp72) expression and activity on stress-induced apoptosis in CD30(+) NPM-ALK(+) anaplastic large-cell lymphomas.
Leukemia. 2012 Jan 6;
Authors: Bonvini P, Zorzi E, Mussolin L, Pillon M, Romualdi C, Peron M, d’Amore ES, Lamant L, Rosolen A
Abstract
Understanding the mechanisms that control stress-induced apoptosis is critical to explain how tumours respond to treatment, as cancer cells frequently escape drug toxicity by regulating stress response through heat shock protein (HSP) expression. The overexpression of Hsp72, in particular, results in increased incidence of cell transformation, and correlates with poor prognosis in a wide range of cancers. We have shown that Hsp72 assists folding of oncogenic NPM-ALK kinase in anaplastic large-cell lymphomas (ALCLs), but its role in the maintenance of the malignant phenotype remains uncertain. Therefore, we assessed Hsp72 expression in ALCLs, investigating more in detail the mechanisms that regulate its status and activity. We found that Hsp72 is unique among the HSPs involved in tumourigenesis to be overexpressed in ALK(+) tumours and cell lines and to be induced by stress. Different from other HSPs, Hsp72 prevents cell injury, Bax activation and death by apoptosis in ALK(+) cells, acting both upstream and downstream of mitochondria. Conversely, Hsp72 is underexpressed in ALK(-) ALCL cells, and it is unable to protect cells from apoptosis under stress. Moreover, when Hsp72 expression is reduced following NPM-ALK inhibition, lymphoma cells undergo apoptosis, demonstrating the importance of Hsp72 in regulating ALCL stress response and drug sensitivity.Leukemia advance online publication, 6 January 2012; doi:10.1038/leu.2011.367.
PMID: 22289917 [PubMed - as supplied by publisher]
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