TY  - JOUR
AB  - BACKGROUND: The coiled-coil domain containing 22/coiled-coil domain containing 93/copper metabolism MURR1 domains (CCC) complex is required for the transport of low-density lipoprotein receptor (LDLR) and LRP1 (LDLR-related protein 1) from endosomes to the cell surface of hepatocytes. Impaired functioning of hepatocytic CCC causes hypercholesterolemia in mice, dogs, and humans. Retriever, a protein complex consisting of subunits VPS26C, VPS35L, and VPS29, is associated with CCC, but its role in endosomal lipoprotein receptor transport is unclear. We here investigated the contribution of retriever to hepatocytic lipoprotein receptor recycling and plasma lipids regulation. METHODS: Using somatic CRISPR/Cas9 gene editing, we generated liver-specific VPS35L or VPS26C-deficient mice. We determined total and surface levels of LDLR and LRP1 and plasma lipids. In addition, we studied the protein levels and composition of CCC and retriever. RESULTS: Hepatocyte VPS35L deficiency reduced VPS26C levels but had minimal impact on CCC composition. VPS35L deletion decreased hepatocytic surface expression of LDLR and LRP1, accompanied by a 21% increase in plasma cholesterol levels. Hepatic VPS26C ablation affected neither levels of VPS35L and CCC subunits, nor plasma lipid concentrations. However, VPS26C deficiency increased hepatic LDLR protein levels by 2-fold, probably compensating for reduced LRP1 functioning, as we showed in VPS26C-deficient hepatoma cells. Upon PCSK9 (proprotein convertase subtilisin/kexin type 9)-mediated LDLR elimination, VPS26C ablation delayed postprandial triglyceride clearance and increased plasma TG levels by 26%. CONCLUSIONS: Our study suggests that VPS35L is shared between retriever and CCC to facilitate LDLR and LRP1 transport from endosomes to the cell surface. Conversely, retriever subunit VPS26C selectively transports LRP1, but not LDLR, and thereby may control hepatic uptake of postprandial TG-rich lipoprotein remnants.
AU  - Vos, D.Y.*
AU  - Wijers, M.*
AU  - Smit, M.*
AU  - Huijkman, N.*
AU  - Kloosterhuis, N.J.*
AU  - Wolters, J.C.*
AU  - Tissink, J.J.
AU  - Pronk, A.C.M.*
AU  - Kooijman, S.*
AU  - Rensen, P.C.N.*
AU  - Kuivenhoven, J.A.*
AU  - Van De Sluis, B.*
C1  - 66685
C2  - 53272
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - e29-e45
TI  - Cargo-specific role for retriever subunit VPS26C in hepatocyte lipoprotein receptor recycling to control postprandial triglyceride-rich lipoproteins.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 43
IS  - 1
PB  - Lippincott Williams & Wilkins
PY  - 2022
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Objective- Expression of the chemokine-like receptor ChemR23 (chemerin receptor 23) has been specifically attributed to plasmacytoid dendritic cells (pDCs) and macrophages and ChemR23 has been suggested to mediate an inflammatory immune response in these cells. Because chemokine receptors are important in perpetuating chronic inflammation, we aimed to establish the role of ChemR23-deficiency on macrophages and pDCs in atherosclerosis. Approach and Results- ChemR23-knockout/knockin mice expressing eGFP (enhanced green fluorescent protein) were generated and after crossing with apolipoprotein E-deficient (Apoe(-/-) ChemR23(e/e)) animals were fed a western-type diet for 4 and 12 weeks. Apoe(-/-) ChemR23(e/e) mice displayed reduced lesion formation and reduced leukocyte adhesion to the vessel wall after 4 weeks, as well as diminished plaque growth, a decreased number of lesional macrophages with an increased proportion of M2 cells and a less inflammatory lesion composition after 12 weeks of western-type diet feeding. Hematopoietic ChemR23-deficiency similarly reduced atherosclerosis. Additional experiments revealed that ChemR23-deficiency induces an alternatively activated macrophage phenotype, an increased cholesterol efflux and a systemic reduction in pDC frequencies. Consequently, expression of the pDC marker SiglecH in atherosclerotic plaques of Apoe(-/-) ChemR23(e/e) mice was declined. ChemR23-knockout pDCs also exhibited a reduced migratory capacity and decreased CCR (CC-type chemokine receptor)7 expression. Finally, adoptive transfer of sorted wild-type and knockout pDCs into Apoe(-/-) recipient mice revealed reduced accumulation of ChemR23-deficient pDCs in atherosclerotic lesions. Conclusions- Hematopoietic ChemR23-deficiency increases the proportion of alternatively activated M2 macrophages in atherosclerotic lesions and attenuates pDC homing to lymphatic organs and recruitment to atherosclerotic lesions, which synergistically restricts atherosclerotic plaque formation and progression.
AU  - van der Vorst, E.P.C.*
AU  - Mandl, M.*
AU  - Müller, M.*
AU  - Neideck, C.*
AU  - Jansen, Y.*
AU  - Hristov, M.*
AU  - Gencer, S.*
AU  - Peters, L.J.F.*
AU  - Meiler, S.*
AU  - Feld, M.*
AU  - Geiselhöringer, A.-L.
AU  - de Jong, R.J.
AU  - Ohnmacht, C.
AU  - Noels, H.*
AU  - Soehnlein, O.*
AU  - Drechsler, M.*
AU  - Weber, C.*
AU  - Döring, Y.*
C1  - 55566
C2  - 46239
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 685-693
TI  - Hematopoietic ChemR23 (Chemerin Receptor 23) fuels atherosclerosis by sustaining an M1 macrophage-phenotype and guidance of plasmacytoid dendritic  cells to murine lesions-brief report.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 39
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2019
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Objective Lp(a) (lipoprotein(a)) concentrations are widely genetically determined by the LPA isoforms and show 5-fold interpopulation differences. Two- to 3-fold differences have been reported even within Europe. Finns represent a distinctive population isolate within Europe and have been repeatedly reported to present lower Lp(a) concentrations than Central Europeans. The significance of this finding was unclear for a long time because of the difficult comparability of Lp(a) assays. Recently, a large standardized study in >50000 individuals from 7 European populations confirmed this observation but could not provide insights into the causes.Approach and Results We investigated Lp(a) concentrations, LPA isoforms, and genotypes of established genetic variants affecting Lp(a) concentrations (LPA variants, APOE isoforms, and PCSK9 R46L) in the Finnish YFS (Cardiovascular Risk in Young Finns Study) population (n=2281) and 3 Non-Finnish Central European populations (n=10003). We observed approximate to 50% lower Lp(a) concentrations in Finns. The isoform distribution was shifted toward longer isoforms, and the percentage of low-molecular-weight isoform carriers was reduced. Most interestingly, however, Lp(a) was reduced in each single-isoform group. In contrast to the known inverse relationship between LPA isoforms and Lp(a) concentrations, especially very short isoforms presented unexpectedly low Lp(a) concentrations in Finns. The investigated genetic variants, as well as age, sex, and renal function, explained 71.8% of the observed population differences.Conclusions The population differences in Lp(a) concentrations between Finnish and Central European populations originate not only from a different LPA isoform distribution but suggest the existence of novel functional variation in the small-isoform range.
AU  - Erhart, G.*
AU  - Lamina, C.*
AU  - Lehtimäki, T.*
AU  - Marques-Vidal, P.*
AU  - Kähönen, M.*
AU  - Vollenweider, P.*
AU  - Raitakari, O.T.*
AU  - Waeber, G.*
AU  - Thorand, B.
AU  - Strauch, K.
AU  - Gieger, C.
AU  - Meitinger, T.
AU  - Peters, A.
AU  - Kronenberg, F.*
AU  - Coassin, S.*
C1  - 53298
C2  - 44574
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1230-1241
TI  - Genetic factors explain a major fraction of the 50% lower lipoprotein(a) concentrations in Finns.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 38
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2018
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Objective—Neutrophils accumulate in early atherosclerotic lesions and promote lesion growth. In this study, we evaluated an elastase-specific near-infrared imaging agent for molecular imaging using hybrid fluorescence molecular tomography/x-ray computed tomography. Approach and Results—Murine neutrophils were isolated from bone marrow and incubated with the neutrophil-targeted near-infrared imaging agent Neutrophil Elastase 680 FAST for proof of principle experiments, verifying that the elastase-targeted fluorescent agent is specifically cleaved and activated by neutrophil content after lysis or cell stimulation. For in vivo experiments, low-density lipoprotein receptor–deficient mice were placed on a Western-type diet and imaged after 4, 8, and 12 weeks by fluorescence molecular tomography/x-ray computed tomography. Although this agent remains silent on injection, it produces fluorescent signal after cleavage by neutrophil elastase. After hybrid fluorescence molecular tomography/x-ray computed tomography imaging, mice were euthanized for whole-body cryosectioning and histological analyses. The in vivo fluorescent signal in the area of the aortic arch was highest after 4 weeks of high-fat diet feeding and decreased at 8 and 12 weeks. Ex vivo whole-body cryoslicing confirmed the fluorescent signal to locate to the aortic arch and to originate from the atherosclerotic arterial wall. Histological analysis demonstrated the presence of neutrophils in atherosclerotic lesions. Conclusions—This study provides evidence that elastase-targeted imaging can be used for in vivo detection of early atherosclerosis. This imaging approach may harbor potential in the clinical setting for earlier diagnosis and treatment of atherosclerosis.  
AU  - Glinzer, A.*
AU  - Ma, X.
AU  - Prakash, J.
AU  - Kimm, M.A.*
AU  - Lohöfer, F.*
AU  - Kosanke, K.*
AU  - Pelisek, J.*
AU  - Thon, M.*
AU  - Vorlova, S.*
AU  - Heinze, K.G.*
AU  - Eckstein, H.H.*
AU  - Gee, M.W.*
AU  - Ntziachristos, V.
AU  - Zernecke, A.*
AU  - Wildgruber, M.*
C1  - 50270
C2  - 42073
SP  - 525-533
TI  - Targeting elastase for molecular imaging of early atherosclerotic lesions.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 37
IS  - 3
PY  - 2017
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Interleukin (IL)-1β represents a key cytokine in the development of cardiovascular disease (CVD). IL-1β is counter-regulated by IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor. This study aimed to identify population-based studies on circulating IL-1RA and incident CVD in a systematic review, estimate the association between IL-1RA and incident CVD in a meta-analysis, and to test whether the association between IL-1RA and incident CVD is explained by other inflammation-related biomarkers in the MONICA/KORA Augsburg case-cohort study (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg). APPROACH AND RESULTS: We performed a systematic literature search and identified 5 cohort studies on IL-1RA and incident CVD in addition to the MONICA/KORA Augsburg case-cohort study for a meta-analysis based on a total of 1855 CVD cases and 18 745 noncases with follow-up times between 5 and 16 years. The pooled standardized hazard ratio (95% confidence interval) for incident CVD was 1.11 (1.06-1.17) after adjustment for age, sex, anthropometric, metabolic, and lifestyle factors (P<0.0001). There was no heterogeneity in effect sizes (I(2)=0%; P=0.88). More detailed analyses in the MONICA/KORA study showed that the excess risk for CVD was attenuated by ≥10% after additional separate adjustment for serum levels of high-sensitivity C-reactive protein, IL-6, myeloperoxidase, soluble E-selectin, or soluble intercellular adhesion molecule-1. CONCLUSIONS: Serum IL-1RA levels were positively associated with risk of CVD after adjustment for multiple confounders in a meta-analysis of 6 population-based cohorts. This association may at least partially reflect a response to triggers inducing subclinical inflammation, oxidative stress, and endothelial activation.
AU  - Herder, C.*
AU  - de Las Heras Gala, T.
AU  - Carstensen-Kirberg, M.*
AU  - Huth, C.
AU  - Zierer, A.
AU  - Wahl, S.
AU  - Sudduth-Klinger, J.*
AU  - Kuulasmaa, K.A.
AU  - Peretz, D.*
AU  - Ligthart, S.
AU  - Bongaerts, B.W.C.*
AU  - Dehghan, A.*
AU  - Ikram, M.A.
AU  - Jula, A.*
AU  - Kee, F.*
AU  - Pietilä, A.*
AU  - Saarela, O.*
AU  - Zeller, T.*
AU  - Blankenberg, S.*
AU  - Meisinger, C.
AU  - Peters, A.
AU  - Roden, M.*
AU  - Salomaa, V.*
AU  - Koenig, W.*
AU  - Thorand, B.
C1  - 50971
C2  - 42874
SP  - 1222-1227
TI  - Circulating levels of interleukin 1-receptor antagonist and risk of  cardiovascular disease: Meta-analysis of six population-based cohorts.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 37
IS  - 6
PY  - 2017
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Drug-eluting coronary stents reduce restenosis rate and late lumen loss compared with bare-metal stents; however, drug-eluting coronary stents may delay vascular healing and increase late stent thrombosis. The peroxisome proliferator-activated receptor-delta (PPARδ) exhibits actions that could favorably influence outcomes after drug-eluting coronary stents placement. APPROACH AND RESULTS: Here, we report that PPARδ ligand-coated stents strongly reduce the development of neointima and luminal narrowing in a rabbit model of experimental atherosclerosis. Inhibition of inflammatory gene expression and vascular smooth muscle cell (VSMC) proliferation and migration, prevention of thrombocyte activation and aggregation, and proproliferative effects on endothelial cells were identified as key mechanisms for the prevention of restenosis. Using normal and PPARδ-depleted VSMCs, we show that the observed effects of PPARδ ligand GW0742 on VSMCs and thrombocytes are PPARδ receptor dependent. PPARδ ligand treatment induces expression of pyruvate dehydrogenase kinase isozyme 4 and downregulates the glucose transporter 1 in VSMCs, thus impairing the ability of VSMCs to provide the increased energy demands required for growth factor-stimulated proliferation and migration. CONCLUSIONS: In contrast to commonly used drugs for stent coating, PPARδ ligands not only inhibit inflammatory response and proliferation of VSMCs but also prevent thrombocyte activation and support vessel re-endothelialization. Thus, pharmacological PPARδ activation could be a promising novel strategy to improve drug-eluting coronary stents outcomes.
AU  - Hytönen, J.*
AU  - Leppaenen, O.*
AU  - Braesen, J.H.*
AU  - Schunck, W.H.*
AU  - Müller, D.*
AU  - Jung, F.*
AU  - Mrowietz, C.*
AU  - Jastroch, M.
AU  - von Bergwelt-Baildon, M.*
AU  - Kappert, K.*
AU  - Heuser, A.*
AU  - Drenckhahn, J.D.*
AU  - Pieske, B.*
AU  - Thierfelder, L.*
AU  - Yla-Herttuala, S.*
AU  - Blaschke, F.*
C1  - 48796
C2  - 41408
CY  - Philadelphia
SP  - 1534-1548
TI  - Activation of peroxisome proliferator-activated receptor-δ as novel therapeutic strategy to prevent in-stent restenosis and stent thrombosis.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 36
IS  - 8
PB  - Lippincott Williams & Wilkins
PY  - 2016
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Although the investigation on the importance of mitochondria-derived reactive oxygen species (ROS) in endothelial function has been gaining momentum, little is known on the precise role of the individual components involved in the maintenance of a delicate ROS balance. Here we studied the impact of an ongoing dysregulated redox homeostasis by examining the effects of endothelial cell-specific deletion of murine thioredoxin reductase 2 (Txnrd2), a key enzyme of mitochondrial redox control. APPROACH AND RESULTS: We analyzed the impact of an inducible, endothelial cell-specific deletion of Txnrd2 on vascular remodeling in the adult mouse after femoral artery ligation. Laser Doppler analysis and histology revealed impaired angiogenesis and arteriogenesis. In addition, endothelial loss of Txnrd2 resulted in a prothrombotic, proinflammatory vascular phenotype, manifested as intravascular cellular deposits, as well as microthrombi. This phenotype was confirmed by an increased leukocyte response toward interleukin-1 in the mouse cremaster model. In vitro, we could confirm the attenuated angiogenesis measured in vivo, which was accompanied by increased ROS and an impaired mitochondrial membrane potential. Ex vivo analysis of femoral arteries revealed reduced flow-dependent vasodilation in endothelial cell Txnrd2-deficient mice. This endothelial dysfunction could be, at least partly, ascribed to inadequate nitric oxide signaling. CONCLUSIONS: We conclude that the maintenance of mitochondrial ROS via Txnrd2 in endothelial cells is necessary for an intact vascular homeostasis and remodeling and that Txnrd2 plays a vitally important role in balancing mitochondrial ROS production in the endothelium.
AU  - Kirsch, J.*
AU  - Schneider, H.*
AU  - Pagel, J.I.*
AU  - Rehberg, M.*
AU  - Singer, M.*
AU  - Hellfritsch, J.*
AU  - Chillo, O.*
AU  - Schubert, K.M.*
AU  - Qiu, J.*
AU  - Pogoda, K.*
AU  - Kameritsch, P.*
AU  - Uhl, B.*
AU  - Pircher, J.*
AU  - Deindl, E.*
AU  - Müller, S.*
AU  - Kirchner, T.*
AU  - Pohl, U.*
AU  - Conrad, M.
AU  - Beck, H.*
C1  - 49048
C2  - 41605
CY  - Philadelphia
SP  - 1891-1899
TI  - Endothelial dysfunction, and a prothrombotic, proinflammatory phenotype is caused by loss of mitochondrial thioredoxin reductase in endothelium.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 36
IS  - 9
PB  - Lippincott Williams & Wilkins
PY  - 2016
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Explore aorta B-cell immunity in aged ITALIC! ApoE (-/-) mice. APPROACH AND RESULTS: Transcript maps, fluorescence-activated cell sorting, immunofluorescence analyses, cell transfers, and Ig-ELISPOT assays showed multilayered atherosclerosis B-cell responses in artery tertiary lymphoid organs (ATLOs). Aging-associated aorta B-cell-related transcriptomes were identified, and transcript atlases revealed highly territorialized B-cell responses in ATLOs versus atherosclerotic lesions: ATLOs showed upregulation of bona fide B-cell genes, including Cd19, Ms4a1 (Cd20), Cd79a/b, and Ighm although intima plaques preferentially expressed molecules involved in non-B effector responses toward B-cell-derived mediators, that is, Fcgr3 (Cd16), Fcer1g (Cd23), and the C1q family. ATLOs promoted B-cell recruitment. ATLO B-2 B cells included naive, transitional, follicular, germinal center, switched IgG1(+), IgA(+), and IgE(+) memory cells, plasmablasts, and long-lived plasma cells. ATLOs recruited large numbers of B-1 cells whose subtypes were skewed toward interleukin-10(+) B-1b cells versus interleukin-10(-) B-1a cells. ATLO B-1 cells and plasma cells constitutively produced IgM and IgG and a fraction of plasma cells expressed interleukin-10. Moreover,  ApoE (-/-) mice showed increased germinal center B cells in renal lymph nodes, IgM-producing plasma cells in the bone marrow, and higher IgM and anti-MDA-LDL IgG serum titers. CONCLUSIONS: ATLOs orchestrate dichotomic, territorialized, and multilayered B-cell responses in the diseased aorta; germinal center reactions indicate generation of autoimmune B cells within the diseased arterial wall during aging.
AU  - Srikakulapu, P.*
AU  - Hu, D.
AU  - Yin, C.*
AU  - Mohanta, S.K.*
AU  - Vineela Bontha, S.*
AU  - Peng, L.*
AU  - Beer, M.*
AU  - Weber, C.*
AU  - McNamara, C.A.*
AU  - Grassia, G.*
AU  - Maffia, P.*
AU  - Manz, R.A.*
AU  - Habenicht, A.J.R.*
C1  - 48461
C2  - 41164
CY  - Philadelphia
SP  - 1174-1185
TI  - Artery tertiary lymphoid organs control multilayered territorialized atherosclerosis B-cell responses in aged ApoE-/- mice.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 36
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2016
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Objective Recent genome-wide association studies of coronary artery disease (CAD) have revealed 58 genome-wide significant and 148 suggestive genetic loci. However, the molecular mechanisms through which they contribute to CAD and the clinical implications of these findings remain largely unknown. We aim to retrieve gene subnetworks of the 206 CAD loci and identify and prioritize candidate regulators to better understand the biological mechanisms underlying the genetic associations. Approach and Results We devised a new integrative genomics approach that incorporated (1) candidate genes from the top CAD loci, (2) the complete genetic association results from the 1000 genomes-based CAD genome-wide association studies from the Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease consortium, (3) tissue-specific gene regulatory networks that depict the potential relationship and interactions between genes, and (4) tissue-specific gene expression patterns between CAD patients and controls. The networks and top-ranked regulators according to these data-driven criteria were further queried against literature, experimental evidence, and drug information to evaluate their disease relevance and potential as drug targets. Our analysis uncovered several potential novel regulators of CAD such as LUM and STAT3, which possess properties suitable as drug targets. We also revealed molecular relations and potential mechanisms through which the top CAD loci operate. Furthermore, we found that multiple CAD-relevant biological processes such as extracellular matrix, inflammatory and immune pathways, complement and coagulation cascades, and lipid metabolism interact in the CAD networks. Conclusions Our data-driven integrative genomics framework unraveled tissue-specific relations among the candidate genes of the CAD genome-wide association studies loci and prioritized novel network regulatory genes orchestrating biological processes relevant to CAD.
AU  - Zhao, Y.*
AU  - Chen, J.*
AU  - Freudenberg, J.M.*
AU  - Meng, Q.*
AU  - CARDIoGRAM Consortium (Döring, A.
AU  - Klopp, N.)
AU  - Rajpal, D.K.*
AU  - Yang, X.*
C1  - 48672
C2  - 41282
CY  - Philadelphia
SP  - 928-941
TI  - Network-based identification and prioritization of key regulators of coronary artery disease loci.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 36
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2016
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Objective Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Approaches and Results Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15502 cases/55730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix (ECM) integrity, innate immunity, axon guidance, and signaling by PDRF (platelet-derived growth factor), NOTCH, and the transforming growth factor-/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (eg, semaphoring-regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared with random networks (P<0.001). Network centrality analysis (degree and betweenness) further identified genes (eg, NCAM1, FYN, FURIN, etc) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. Conclusions These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD.
AU  - Ghosh, S.*
AU  - Vivar, J.*
AU  - Nelson, C.P.*
AU  - Willenborg, C.*
AU  - Segrè, A.V.*
AU  - Maekinen, V.*
AU  - Nikpay, M.*
AU  - Erdmann, J.*
AU  - Blankenberg, S.*
AU  - O'Donnell, C.*
AU  - Maerz, W.*
AU  - Laaksonen, R.*
AU  - Stewart, A.F.R.*
AU  - Epstein, S.E.*
AU  - Shah, S.H.*
AU  - Granger, C.B.*
AU  - Hazen, S.L.*
AU  - Kathiresan, S.*
AU  - Reilly, M.P.*
AU  - CARDIoGRAM Consortium (Döring, A.
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Peters, A.
AU  - Wichmann, H.-E.)
AU  - Yang, X.*
AU  - Quertermous, T.*
AU  - Samani, N.J.*
AU  - Schunkert, H.*
AU  - Assimes, T.L.*
AU  - McPherson, R.*
C1  - 46403
C2  - 37756
CY  - Philadelphia
SP  - 1712-1722
TI  - Systems genetics analysis of genome-wide association study reveals novel associations between key biological processes and coronary artery disease.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 35
IS  - 7
PB  - Lippincott Williams & Wilkins
PY  - 2015
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The enzyme heme oxygenase-1 (HO-1) exerts cytoprotective effects in response to various cellular stressors. A variable number tandem repeat polymorphism in the HO-1 gene promoter region has previously been linked to cardiovascular disease. We examined this association prospectively in the general population. APPROACH AND RESULTS: Incidence of stroke, myocardial infarction, or vascular death was registered between 1995 and 2010 in 812 participants of the Bruneck Study aged 45 to 84 years (49.4% males). Carotid atherosclerosis progression was quantified by high-resolution ultrasound. HO-1 variable number tandem repeat length was determined by polymerase chain reaction. Subjects with ≥32 tandem repeats on both HO-1 alleles compared with the rest of the population (recessive trait) featured substantially increased cardiovascular disease risk (hazard ratio [95% confidence interval], 5.45 [2.39, 12.42]; P<0.0001), enhanced atherosclerosis progression (median difference in atherosclerosis score [interquartile range], 2.1 [0.8, 5.6] versus 0.0 [0.0, 2.2] mm; P=0.0012), and a trend toward higher levels of oxidized phospholipids on apolipoprotein B-100 (median oxidized phospholipids/apolipoprotein B level [interquartile range], 11364 [4160, 18330] versus 4844 [3174, 12284] relative light units; P=0.0554). Increased cardiovascular disease risk in those homozygous for ≥32 repeats was also detected in a pooled analysis of 7848 participants of the Bruneck, SAPHIR, and KORA prospective studies (hazard ratio [95% confidence interval], 3.26 [1.50, 7.33]; P=0.0043). CONCLUSIONS: This study found a strong association between the HO-1 variable number tandem repeat polymorphism and cardiovascular disease risk confined to subjects with a high number of repeats on both HO-1 alleles and provides evidence for accelerated atherogenesis and decreased antioxidant defense in this vascular high-risk group.
AU  - Pechlaner, R.*
AU  - Willeit, P.*
AU  - Summerer, M.*
AU  - Santer, P.
AU  - Egger, G.*
AU  - Kronenberg, F.*
AU  - Demetz, E.*
AU  - Weiss, G.*
AU  - Tsimikas, S.*
AU  - Witztum, J.L.*
AU  - Willeit, K.*
AU  - Iglseder, B.*
AU  - Paulweber, B.*
AU  - Kedenko, L.*
AU  - Haun, M.*
AU  - Meisinger, C.
AU  - Gieger, C.
AU  - Müller-Nurasyid, M.
AU  - Peters, A.
AU  - Willeit, J.*
AU  - Kiechl, S.*
C1  - 32652
C2  - 35201
SP  - 229-236
TI  - Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with progressive atherosclerosis and incident cardiovascular disease.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 35
IS  - 1
PY  - 2015
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Arterial injury stimulates remodeling responses that, when excessive, lead to stenosis. These responses are influenced by integrin signaling in vascular smooth muscle cells (VSMCs). Microfibrillar-associated protein 4 (MFAP4) is an integrin ligand localized to extracellular matrix fibers in the vascular wall. The role of MFAP4 in vascular biology is unknown. We aimed to test the hypothesis that MFAP4 would enhance integrin-dependent VSMC activation. APPROACH AND RESULTS: We produced Mfap4-deficient (Mfap4(-/-)) mice and performed carotid artery ligation to explore the role of MFAP4 in vascular biology in vivo. Furthermore, we investigated the effects of MFAP4 in neointimal formation ex vivo and in primary VSMC and monocyte cultures in vitro. When challenged with carotid artery ligation, Mfap4(-/-) mice exhibited delayed neointimal formation, accompanied by early reduction in the number of proliferating medial and neointimal cells, as well as infiltrating leukocytes. Delayed neointimal formation was associated with decreased cross-sectional area of ligated Mfap4(-/-) carotid arteries resulting in lumen narrowing 28 days after ligation. MFAP4 blockade prohibited the formation of neointimal hyperplasia ex vivo. Moreover, we demonstrated that MFAP4 is a ligand for integrin αVβ3 and mediates VSMC phosphorylation of focal adhesion kinase, migration, and proliferation in vitro. MFAP4-dependent VSMC activation was reversible by treatment with MFAP4-blocking antibodies and inhibitors of focal adhesion kinase and downstream kinases. In addition, we showed that MFAP4 promotes monocyte chemotaxis in integrin αVβ3-dependent manner. CONCLUSIONS: MFAP4 regulates integrin αVβ3-induced VSMC proliferation and migration, as well as monocyte chemotaxis, and accelerates neointimal hyperplasia after vascular injury.
AU  - Schlosser, A.*
AU  - Pilecki, B.*
AU  - Hemstra, L.E.*
AU  - Kejling, K.*
AU  - Kristmannsdottir, G.B.*
AU  - Wulf-Johansson, H.*
AU  - Moeller, J.B.*
AU  - Füchtbauer, E.M.*
AU  - Nielsen, O.*
AU  - Kirketerp-Møller, K.*
AU  - Dubey, L.K.*
AU  - Hansen, P.B.*
AU  - Stubbe, J.*
AU  - Wrede, C.*
AU  - Hegermann, J.*
AU  - Ochs, M.*
AU  - Rathkolb, B.
AU  - Schrewe, A.
AU  - Bekeredjian, R.*
AU  - Wolf, E.*
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Lindholt, J.S.*
AU  - Holmskov, U.*
AU  - Sorensen, G.L.*
C1  - 47300
C2  - 39327
SP  - 122-133
TI  - MFAP4 promotes vascular smooth muscle migration, proliferation and accelerates neointima formation.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 36
IS  - 1
PY  - 2015
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Objective Elevated levels of plasma trimethylamine N-oxide (TMAO), the product of gut microbiome and hepatic-mediated metabolism of dietary choline and l-carnitine, have recently been identified as a novel risk factor for the development of atherosclerosis in mice and humans. The goal of this study was to identify the genetic factors associated with plasma TMAO levels. Approach and Results We used comparative genome-wide association study approaches to discover loci for plasma TMAO levels in mice and humans. A genome-wide association study in the hybrid mouse diversity panel identified a locus for TMAO levels on chromosome 3 (P=2.37x10(-6)) that colocalized with a highly significant (P=1.07x10(-20)) cis-expression quantitative trait locus for solute carrier family 30 member 7. This zinc transporter could thus represent 1 positional candidate gene responsible for the association signal at this locus in mice. A genome-wide association study for plasma TMAO levels in 1973 humans identified 2 loci with suggestive evidence of association (P=3.0x10(-7)) on chromosomes 1q23.3 and 2p12. However, genotyping of the lead variants at these loci in 1892 additional subjects failed to replicate their association with plasma TMAO levels. Conclusions The results of these limited observational studies indicate that, at least in humans, genes play a marginal role in determining TMAO levels and that any genetic effects are relatively weak and complex. Variation in diet or the repertoire of gut microbiota may be more important determinants of plasma TMAO levels in mice and humans, which should be investigated in future studies.
AU  - Hartiala, J.*
AU  - Bennett, B.J.*
AU  - Tang, W.H.W.*
AU  - Wang, Z.*
AU  - Stewart, A.F.R.*
AU  - Roberts, R.*
AU  - McPherson, R.*
AU  - CARDIoGRAM Consortium (Döring, A.
AU  - Illig, T.
AU  - Klopp, N.
AU  - Meisinger, C.
AU  - Meitinger, T.
AU  - Peters, A.
AU  - Wichmann, H.-E.)
AU  - Lusis, A.*
AU  - Hazen, S.L.*
AU  - Allayee, H.*
C1  - 31649
C2  - 34613
CY  - Philadelphia
SP  - 1307-1313
TI  - Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and l-carnitine.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 34
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: To determine whether the level of lysophosphatidylcholine (lysoPC) generated by lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with severity of inflammation in human atherosclerotic plaques. Elevated plasma Lp-PLA2 is associated with increased cardiovascular risk. Lp-PLA2 inhibition reduces atherosclerosis. Lp-PLA2 hydrolyzes low-density lipoprotein-oxidized phospholipids generating lysoPCs. According to in vitro studies, lysoPCs are proinflammatory but the association between their generation and plaque inflammation remains unknown. METHODS AND RESULTS: Inflammatory activity in carotid plaques (162 patients) was determined immunohistochemically and by analyzing cytokines in homogenates (multiplex immunoassay). LysoPCs were quantified using mass spectrometry and Lp-PLA2 and the lysoPC metabolite lysophosphatidic acid (LPA) by ELISA. There was a strong correlation among lysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 in plaques. LysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 correlated with interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, regulated on activation normal T-cell expressed and secreted, and tumor necrosis factor-α in plaques. High lysoPC and Lp-PLA2 correlated with increased plaque macrophages and lipids and with low content of smooth muscle cells, whereas LPA only correlated with plaque macrophages. Lp-PLA2, lysoPC 16:0, 18:0, and 18:1, but not LPA were higher in symptomatic than in asymptomatic plaques. CONCLUSIONS: The associations among Lp-PLA2, lysoPCs, LPA, and proinflammatory cytokines in human plaques suggest that lysoPCs play a key role in plaque inflammation and vulnerability. Our findings support Lp-PLA2 inhibition as a possible strategy for the prevention of cardiovascular disease.
AU  - Gonçalves, I.*
AU  - Edsfeldt, A.*
AU  - Ko, N.Y.*
AU  - Grufman, H.*
AU  - Berg, K.*
AU  - Björkbacka, H.*
AU  - Nitulescu, M.*
AU  - Persson, A.*
AU  - Nilsson, M.*
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Nilsson, J.*
C1  - 7480
C2  - 29740
SP  - 1505-1512
TI  - Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 32
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2012
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Cord blood-derived human endothelial colony-forming cells (ECFCs) bear a high proliferative capacity and potently enhance tissue neovascularization in vivo. Here, we investigated whether the leading mechanism for the functional improvement relates to their physical vascular incorporation or perivascular paracrine effects and whether the effects can be further enhanced by dual-cell-based therapy, including mesenchymal stem cells (MSCs). METHODS AND RESULTS: ECFCs or MSCs were lentivirally transduced with thymidine kinase suicide gene driven by the endothelial-specific vascular endothelial growth factor 2 (kinase insert domain receptor) promoter and evaluated in a hindlimb ischemia model. ECFCs and MSCs enhanced neovascularization after ischemic events to a similar extent. Dual therapy using ECFCs and MSCs further enhanced neovascularization. Mechanistically, 3 weeks after induction of ischemia followed by cell therapy, ganciclovir-mediated elimination of kinase insert domain receptor(+) cells completely reversed the therapeutic effect of ECFCs but not that of MSCs. Histological analysis revealed that ganciclovir effectively eliminated ECFCs incorporated into the vasculature. CONCLUSIONS: Endothelial-specific suicide gene technology demonstrates distinct mechanisms for ECFCs and MSCs, with complete abolishment of ECFC-mediated effects, whereas MSC-mediated effects remained unaffected. These data strengthen the notion that a dual-cell-based therapy represents a promising approach for vascular regeneration of ischemic tissue.
AU  - Schwarz, T.M.*
AU  - Leicht, S.F.*
AU  - Radic, T.*
AU  - Rodriguez-Araboalaza, I.*
AU  - Hermann, P.C.*
AU  - Berger, F.*
AU  - Saif, J.*
AU  - Böcker, W.*
AU  - Ellwart, J.W.
AU  - Aicher, A.*
AU  - Heeschen, C.*
C1  - 7109
C2  - 29595
SP  - E13-E21
TI  - Vascular incorporation of endothelial colony-forming cells is essential for functional recovery of murine ischemic tissue following cell therapy.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 32
IS  - 2
PB  - Lippincott Williams&Wilkins
PY  - 2012
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Low and nontoxic proteasome inhibition has anti-inflammatory, antiproliferative, and antioxidative effects on vascular cells in vitro and in vivo. We hypothesized that low-dose inhibition of the proteasome could provide antiatherogenic protection. The present study investigated the effect of low-dose proteasome inhibition on early lesion formation in low-density lipoprotein receptor-deficient mice fed a Western-type diet. METHODS AND RESULTS: Male low-density lipoprotein receptor-deficient mice, 10 weeks old, were fed a Western-type diet for 6 weeks with intraperitoneal injections of bortezomib or solvent. Bortezomib was injected at a dose of 50 μg/kg body weight. Cholesterol plasma levels were not affected by bortezomib treatment. En face Oil Red O staining of aortae and aortic root cryosections demonstrated significant reduction of atherosclerotic lesion coverage in bortezomib-treated animals. Bortezomib significantly reduced vascular cellular adhesion molecule-1 expression and macrophage infiltration as shown by histological analysis. Bortezomib treatment resulted in a significant reduction of superoxide content, lipid peroxidation and protein oxidation products, serum levels of monocyte chemoattractant protein-1, and interleukin-6. Gene expression microarray analysis showed that expressional changes induced by Western-type diet were attenuated by treatment with low-dose bortezomib. CONCLUSIONS: Low-dose proteasome inhibition exerts antioxidative and anti-inflammatory effects and attenuates development of atherosclerotic lesions in low-density lipoprotein receptor-deficient mice.
AU  - Wilck, N.*
AU  - Fechner, M.*
AU  - Dreger, H.*
AU  - Hewing, B.*
AU  - Arias, A.*
AU  - Meiners, S.
AU  - Baumann, G.*
AU  - Stangl, V.*
AU  - Stangl, K.*
AU  - Ludwig, A.*
C1  - 7471
C2  - 29731
SP  - 1418-1426
TI  - Attenuation of early atherogenesis in low-density lipoprotein receptor-deficient mice by proteasome inhibition.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 32
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2012
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: To examine the association between genomewide association study-based diabetes mellitus-related single-nucleotide polymorphisms (SNPs) and coronary artery calcification (CAC), a valid risk factor for coronary heart disease, in a large, unselected, population-based cohort. METHODS AND RESULTS: We genotyped 11 validated genomewide association study-based diabetes SNPs in 4459 participants of the Heinz Nixdorf Recall Study. We applied generalized linear regression models to explore the impact of the diabetes SNPs on CAC and to jointly model the effect of the SNPs and CAC on diabetes status. We observed a significant association between cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) variant rs564398 and quantitative CAC (P=1.81 x 10(-5) and adjusted P=4.02 x 10(-4); odds ratio for the presence of CAC, 1.12 [95% CI, 1.02 to 1.25]). Moreover, we observed no strong impact of CAC on diabetes risk in the presence of the other genetic variants. CONCLUSIONS: We show that a genetic variant near CDKN2A/2B that has been reported to be strongly associated with diabetes is strongly associated with CAC. In contrast, variants near insulin-like growth factor-binding protein 2 (IGFBP2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), solute carreir family 30 (zinc transporter), member 8 (SLC30A8), hematopoietically-expressed homeobox (HHEX), and transcription factor 7-like2 (TCF7L2) were clearly associated with diabetes; no evidence for an association to CAC was observable. This differential association pattern underlines the potential of endophenotypes, such as CAC, to extend the scope of disease outcome associations.
AU  - Pechlivanis, S.*
AU  - Scherag, A.*
AU  - Mühleisen, T.W.*
AU  - Möhlenkamp, S.*
AU  - Horsthemke, B.*
AU  - Boes, T.*
AU  - Bröcker-Preuss, M.*
AU  - Mann, K.*
AU  - Erbel, R.*
AU  - Jöckel, K.-H.*
AU  - Nöthen, M.M.*
AU  - Moebus, S.*
AU  - Heinz Nixdorf Recall Study Investigative Group (Löwel, H.)
C1  - 32352
C2  - 34982
SP  - 1867-1872
TI  - Coronary artery calcification and its relationship to validated genetic variants for diabetes mellitus assessed in the Heinz Nixdorf recall cohort.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 30
IS  - 9
PY  - 2010
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Background-Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. Methods and Results-We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81x10(-21)). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44x10(-7)), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02x10(-3)), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34x10(-4)). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P = 0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86x10(-5)) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. ConclusionsThe findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.
AU  - Amouyel, P.*
AU  - Arveiler, D.*
AU  - Boekholdt, S.M.*
AU  - Braund, P.*
AU  - Bruse, P.*
AU  - Bumpstead, S.J.*
AU  - Bugert, P.*
AU  - Cambien, F.*
AU  - Danesh, J.*
AU  - Deloukas, P.*
AU  - Döring, A.
AU  - Ducimetiere, P.*
AU  - Dunn, R.M.*
AU  - El Mokhtari, N.-E.*
AU  - Erdmann, J.*
AU  - Evans, A.*
AU  - Ewels, P.*
AU  - Ferrieres, J.*
AU  - Fischer, M.*
AU  - Frossard, P.*
AU  - Garner, S.*
AU  - Gieger, C.
AU  - Gohri, M.J.R.*
AU  - Goodall, A.H.*
AU  - Grosshennig, A.*
AU  - Hall, A.*
AU  - Hardwick, R.*
AU  - Haukijärvi, A.*
AU  - Hengstenberg, C.*
AU  - Illig, T.
AU  - Karvanen, J.*
AU  - Kastelein, J.*
AU  - Kee, F.*
AU  - Khaw, K.-T.*
AU  - Klüter, H.*
AU  - König, I.R.*
AU  - Kuulasmaa, K.*
AU  - Laiho, P.*
AU  - Luc, G.*
AU  - Marz, W.*
AU  - McGinnis, R.*
AU  - McLaren, W.*
AU  - Meisinger, C.
AU  - Morrison, C.*
AU  - Ou, X.*
AU  - Ouwehand, W.H.*
AU  - Preuss, M.*
AU  - Proust, C.*
AU  - Ravindrarajah, R.*
AU  - Renner, W.*
AU  - Rice, K.*
AU  - Ruidavets, J.-B.*
AU  - Saleheen, D.*
AU  - Salomaa, V.*
AU  - Samani, N.J.*
AU  - Sandhu, M.S.*
AU  - Schäfer, A.S.*
AU  - Scholz, M.*
AU  - Schreiber, S.*
AU  - Schunkert, H.*
AU  - Silander, K.*
AU  - Singh, R.*
AU  - Soranzo, N.*
AU  - Stark, K.*
AU  - Stegmayr, B.*
AU  - Stephens, J.*
AU  - Thompson, J.*
AU  - Tiret, L.*
AU  - Trip, M.D.*
AU  - van der Schoot, E.*
AU  - Virtamo, J.*
AU  - Wareham, N.J.*
AU  - Wichmann, H.-E.
AU  - Wiklund, P.-G.*
AU  - Wright, B.*
AU  - Ziegler, A.*
AU  - Zwaginga, J.-J.*
C1  - 874
C2  - 26128
SP  - 774-780
TI  - Large scale association analysis of novel genetic loci for coronary artery disease.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 29
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2009
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - The purpose of this study was to assess whether increasing serum uric acid (UA) levels are related to cardiovascular disease (CVD) mortality, all-cause mortality, and incident (fatal and nonfatal) myocardial infarction (MI) in men from the general population taking into account C-reactive protein (CRP), a sensitive marker of systemic inflammation. METHODS AND RESULTS: The study was based on 3604 men (45 to 74 years of age) who participated in 1 of the 3 MONICA Augsburg surveys between 1984 and 1995. All participants were prospectively followed within the framework of the Cooperative Health Research in the Region of Augsburg (KORA). Up to December 31, 2002, there occurred 809 total deaths, 359 CVD deaths, and 297 incident MIs. In a Cox model, comparing extreme quartiles of the UA distribution, the hazard ratio for CVD mortality was 1.44 (95% confidence interval [CI] 1.04 to 2.0), and for all-cause mortality it was 1.40 (95% CI 1.13 to 1.74) after adjustment for conventional cardiovascular risk factors, CRP, and diuretic intake. However, UA was not associated with incident MI after multivariable adjustment. CONCLUSIONS: High UA levels were independently associated with CVD mortality as well as all-cause mortality but not with incident MI in middle-aged men from the general population.
AU  - Meisinger, C.
AU  - Koenig, W.*
AU  - Baumert, J.J.
AU  - Döring, A.
C1  - 4571
C2  - 25388
SP  - 1186-1192
TI  - Uric acid levels are associated with all-cause and cardiovascular disease mortality independent of systemic inflammation in men from the general population: The MONICA/KORA cohort study.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 28
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2008
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Thrombus formation after atherosclerotic plaque rupture critically involves the platelet collagen receptor glycoprotein (GP) VI. We investigated the impact of EXP3179, an active metabolite of the angiotensin II type 1 (AT1)-receptor antagonist Losartan (LOS) on GPVI-dependent platelet activation. METHODS AND RESULTS: EXP3179 and LOS but not EXP3174--the major AT1-receptor blocking metabolite of LOS--dose-dependently inhibited collagen-I (P<0.01) and GPVI-dependent platelet aggregation (P<0.01) analyzed by optical aggregometry. Platelet activation was further determined by flow cytometry measuring the expression of platelet PAC-1, an epitope of the activated fibrinogen-receptor complex. EXP3179 and LOS inhibited collagen-I (P<0.01) and GPVI-dependent PAC-1 expression (P<0.01). EXP3179 and LOS but not EXP3174 decreased the adhesion of GPVI-receptor expressing Chinese hamster ovarian cells on collagen-I under arterial shear conditions determined by flow chamber analysis (P<0.01 and P<0.05). EXP3179 also reduced human atherosclerotic plaque material-induced platelet aggregation (P<0.01) in vitro and murine platelet adhesion after acute vessel injury in vivo as determined by intravital microscopy (P<0.01). CONCLUSION: EXP3179 acts as a specific inhibitor of the platelet collagen receptor GPVI independent of AT1-receptor antagonism. Further investigations may clarify its individual potential as a novel pharmacological approach to specifically inhibit atherothrombotic events by GPVI-receptor blockade.
AU  - Grothusen, C.*
AU  - Umbreen, S.*
AU  - Konrad, I.*
AU  - Stellos, K.*
AU  - Schulz, C.*
AU  - Schmidt, B.*
AU  - Kremmer, E.
AU  - Teebken, O.*
AU  - Massberg, S.*
AU  - Luchtefeld, M.*
AU  - Schieffer, B.*
AU  - Gawaz, M.*
C1  - 3808
C2  - 24805
SP  - 1184-1190
TI  - EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism: Potential impact on atherothrombosis.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 27
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2007
SN  - 1079-5642
ER  - 

TY  - JOUR
AU  - Herder, C.*
AU  - Baumert, J.J.
AU  - Thorand, B.
AU  - Martin, S.*
AU  - Löwel, H.
AU  - Kolb, H.*
AU  - Koenig, W.*
C1  - 3066
C2  - 23791
SP  - 2147-2152
TI  - Chemokines and incident coronary heart disease: Results from the MONICA/KORA Augsburg Case-Cohort Study, 1984-2002.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 26
PY  - 2006
SN  - 1079-5642
ER  - 

TY  - JOUR
AU  - Kappert, K.*
AU  - Sparwel, J.*
AU  - Sandin, A.*
AU  - Seiler, A.
AU  - Siebolts, U.*
AU  - Leppänen, O.*
AU  - Rosenkranz, S.*
AU  - Östman, A.*
C1  - 5593
C2  - 24191
SP  - 2644-2651
TI  - Antioxidants relieve phosphatase inhibition and reduce PDGF signaling in cultured VSMCs and in restenosis.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 26
PY  - 2006
SN  - 1079-5642
ER  - 

TY  - JOUR
AU  - König, W.*
AU  - Khuseyinova, N.*
AU  - Baumert, J.J.
AU  - Thorand, B.
AU  - Löwel, H.
AU  - Chambless, L.*
AU  - Meisinger, C.
AU  - Schneider, A.E.
AU  - Martin, S.*
AU  - Kolb, H.*
AU  - Herder, C.*
C1  - 4612
C2  - 24176
SP  - 2745-2751
TI  - Increased concentrations of C-reactive protein and IL-6 but not IL-18 are independently associated with incident coronary events in middle-aged men and women.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 26
PY  - 2006
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Using the Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) database, we investigated prospectively whether increased levels of soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule 1 (sICAM-1), and von Willebrand factor (vWF), all considered to be sensitive markers of endothelial dysfunction, are associated with an increased risk of incident type 2 diabetes mellitus. METHODS AND RESULTS: In a case-cohort study, concentrations of adhesion molecules were measured in stored samples of 532 case subjects and 1712 noncase subjects. VWF was measured in a subsample with available plasma samples (n=191 case and 580 noncase subjects). Men and women with elevated levels of sE-selectin had a significantly increased risk of type 2 diabetes after multivariable adjustment. Hazard ratios (95% CIs) comparing tertile extremes of sE-selectin were 2.63 (1.79 to 3.88) and 1.71 (1.07 to 2.75) for men and women, respectively. Elevated levels of sICAM-1 were also associated with an increased risk of type 2 diabetes; however, the association was not independent of other diabetes risk factors including E-selectin [hazard ratio (95% CI) for tertile 3 versus tertile 1: men, 1.32 (0.89 to 1.96); women, 1.03 (0.64 to 1.67)]. In this study, vWF was not associated with risk of type 2 diabetes. CONCLUSIONS: These data support a role of endothelial dysfunction in the etiology of type 2 diabetes.  
AU  - Thorand, B.
AU  - Baumert, J.J.
AU  - Chambless, L.*
AU  - Meisinger, C.
AU  - Kolb, H.*
AU  - Döring, A.
AU  - Löwel, H.
AU  - König, W.*
C1  - 3489
C2  - 23702
SP  - 398-405
TI  - Elevated markers of endothelial dysfunction predict type 2 diabetes mellitus in middle-aged men and woman from the general population.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 26
IS  - 2
PY  - 2006
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - OBJECTIVE: The acquisition of arterial or venous identity is highlighted in vascular development. Previously, we have reported an embryonic stem (ES) cell differentiation system that exhibits early vascular development using vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2)-positive cells as common vascular progenitors. In this study, we constructively induced differentiation of arterial and venous endothelial cells (ECs) in vitro to elucidate molecular mechanisms of arterial-venous specification. METHODS AND RESULTS: ECs were induced from VEGFR2+ progenitor cells with various conditions. VEGF was essential to induce ECs. Addition of 8bromo-cAMP or adrenomedullin (AM), an endogenous ligand-elevating cAMP, enhanced VEGF-induced EC differentiation. Whereas VEGF alone mainly induced venous ECs, 8bromo-cAMP (or AM) with VEGF supported substantial induction of arterial ECs. Stimulation of cAMP pathway induced Notch signal activation in ECs. The arterializing effect of VEGF and cAMP was abolished in recombination recognition sequence binding protein at the Jkappa site deficient ES cells lacking Notch signal activation or in ES cells treated with gamma-secretase inhibitor. Nevertheless, forced Notch activation by the constitutively active Notch1 alone did not induce arterial ECs. CONCLUSIONS: Adrenomedullin/cAMP is a novel signaling pathway to activate Notch signaling in differentiating ECs. Coordinated signaling of VEGF, Notch, and cAMP is required to induce arterial ECs from vascular progenitors.  
AU  - Yurugi-Kobayashi, T.*
AU  - Itoh, H.*
AU  - Schroeder, T.
AU  - Nakano, A.*
AU  - Narazaki, G.*
AU  - Kita, F.*
AU  - Yanagi, K.*
AU  - Hiraoka-Kanie, M.*
AU  - Inoue, E.*
AU  - Ara, T.*
AU  - Nagasawa, T.*
AU  - Just, U.*
AU  - Nakao, K.*
AU  - Nishikawa, S.*
AU  - Yamashita, J.K.*
C1  - 4821
C2  - 23772
SP  - 1977-1984
TI  - Adrenomedullin/cyclic AMP pathway induces notch activation and differentiation of arterial endothelial cells from vascular progenitors.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 26
IS  - 9
PY  - 2006
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Objective— Premature cardiovascular disease is the leading cause of death in patients with end-stage renal disease treated by hemodialysis (HD). Low-density lipoprotein (LDL) levels are not generally increased in HD patients, but their LDL metabolism is still poorly understood. We therefore investigated the in vivo metabolism of apoB-containing lipoproteins in two different ethnic populations of HD patients and controls. Methods and Results— We performed stable isotope kinetic studies using a primed constant infusion of deuterated leucine in 12 HD patients and 13 healthy controls. Tracer/tracee ratio of apoB was determined by means of gas chromatography/mass spectrometry, and the modeling program SAAMII was used to estimate the fractional catabolic rate (FCR) of apoB. Mean LDL-apoB plasma concentrations were almost identical in both groups (HD: 95±30 mg/dL, controls: 91±40 mg/dL), whereas LDL-apoB FCR was 50% lower in HD patients as compared with controls (0.22±0.12 days−1 versus 0.46±0.20 days−1, P=0.001) with concomitantly decreased production rates of LDL. Compared with controls, intermediate-density lipoprotein (IDL)-apoB FCR was 65% lower (2.87±1.02 days−1 versus 8.89±4.94 days−1, P=0.014), accompanied by 1.5-fold higher IDL-apoB levels in HD. Very low-density lipoprotein metabolism was similar in both study groups. Conclusions— In vivo catabolism of LDL and IDL is severely impaired in HD patients but misleadingly masked by normal plasma cholesterol levels. The resulting markedly prolonged residence times of both IDL and LDL particles might thus significantly contribute to the well-documented high risk for premature cardiovascular disease in HD patients.
AU  - Ikewaki, K.*
AU  - Kronenberg, F.
C1  - 4500
C2  - 23368
SP  - 2615-2622
TI  - Delayed in Vivo Catabolism of Intermediate-Density Lipoprotein and Low-Density Lipoprotein in Hemodialysis Patients as Potential Cause of Premature Atheriosclerosis.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 25
PY  - 2005
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - Plasma viscosity is determined by various macromolecules, eg, fibrinogen, immunoglobulins, and lipoproteins. It may therefore reflect several aspects involved in cardiovascular diseases, including the effects of classic risk factors, hemostatic disturbances, and inflammation. We examined the association of plasma viscosity with the incidence of a first major coronary heart disease event (CHD; fatal and nonfatal myocardial infarction and cardiac death; n=50) in 933 men aged 45 to 64 years of the MONICA project of Augsburg, Germany. The incidence rate was 7.23 per 1000 person-years (95% confidence interval [CI], 5.37 to 9.53), and the subjects were followed up for 8 years. All suspected cases of an incident CHD event were classified according to the MONICA protocol. There was a positive and statistically significant unadjusted relationship between plasma viscosity and the incidence of CHD. The relative risk of CHD events associated with a 1-SD increase in plasma viscosity (0.070 mPa x s) was 1.60 (95% CI, 1.25 to 2.03). After adjustment for age, total cholesterol, high density lipoprotein cholesterol, smoking, blood pressure, and body mass index, the relative risk was reduced only moderately (1.42; 95% CI, 1.09 to 1.86). The relative risk of CHD events for men in the highest quintile of the plasma viscosity distribution in comparison with the lowest quintile was 3.31 (95% CI, 1.19 to 9.25) after adjustment for the aforementioned variables. A large proportion of events (40%) occurred among men in the highest quintile. These findings suggest that plasma viscosity may have considerable potential to identify subjects at risk for CHD events.
AU  - Koenig, W.*
AU  - Sund, M.
AU  - Filipiak, B.
AU  - Döring, A.
AU  - Löwel, H.
AU  - Ernst, E.*
C1  - 24161
C2  - 31447
SP  - 768-772
TI  - Plasma viscosity and the risk of coronary heart disease: Results from the MONICA-Augsburg cohort study, 1984 to 1992.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 18
IS  - 5
PB  - Lippincott Williams 6 Wilkins
PY  - 1998
SN  - 1079-5642
ER  - 

TY  - JOUR
AB  - The incidence of cardiovascular diseases is increased in winter months. Recent studies have shown seasonal changes in plasma viscosity, fibrinogen, and factor VII activity with elevated levels during winter. An increase in these factors generates a "hypercoagulable state," which may lead to a rise in cardiovascular morbidity and mortality. It has been suggested that an increase in upper respiratory infections might be the underlying cause for the raised acute-phase reactants, in particular fibrinogen, during the winter season. We investigated seasonal variations of 26 parameters, determining blood rheology and hemostasis in 16 healthy volunteers (8 men and 8 women) aged 20 to 41 years. They were seen at monthly intervals over a period of 1 year. Seasonal variation with peak fitted values in the winter months was found for plasma viscosity (P < .001 for the seasonal difference), red blood cell deformability (P < .001), whole blood viscosity (P < .001), hemoglobin (P < .001), hematocrit (P < .001), mean corpuscular volume (P = .001), platelet count (P = .01), alpha 1-glycoprotein (P < .001), fibrinogen (measured by immunonephelometry; P < .001), plasminogen activator inhibitor-1 (P = .002), LDL cholesterol (P = .003), and triglyceride levels (P < .001). HDL cholesterol (P < .001) and cortisol (P = .001) showed inverse seasonal patterns, with a maximum during summertime. No statistically significant seasonal variations were seen for red blood cell aggregation, complement factor C4, total cholesterol, ceruloplasmin, haptoglobin, white blood cell count, and plasminogen. These data do not support the hypothesis that increased morbidity and mortality from cardiovascular diseases during winter may be mainly attributable to increased synthesis of acute-phase proteins due to infections. The cause for the seasonal variations in rheological and hemostatic parameters remains unclear and should be studied in more detail.
AU  - Fröhlich, M.*
AU  - Sund, M.
AU  - Russ, S.*
AU  - Hoffmeister, A.*
AU  - Fischer, H.G.*
AU  - Hombach, V.*
AU  - Koenig, W.*
C1  - 24175
C2  - 31456
SP  - 2692-2697
TI  - Seasonal variations of rheological and hemostatic parameters and acute-phase reactants in young, healthy subjects.
JO  - Arterioscler. Thromb. Vasc. Biol.
VL  - 17
IS  - 11
PB  - Amer. Heart Assoc.
PY  - 1997
SN  - 1079-5642
ER  -