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Berlin Brandenburg

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  • 1
    In: Circulation, 2013, Vol.128(6), pp.579-582
    Description: Athero-prone flow promotes inflammation in endothelial cells, and this process is critical for pathogenesis of many chronic inflammatory conditions such as coronary and carotid artery atherosclerosis, as well as abdominal aortic aneurysm. Signal mediators activated by athero-prone (disturbed) flow that have been described include NF-κB and protein kinase C, which is very different from athero-protective (steady laminar) flow1. In this issue a publication from Shyy’s lab shows the critical role of sterol regulatory element binding protein 2 (SREBP2) on athero-prone flow-mediated NLRP3 inflammasome activation2. In particular, they showed that athero-prone flow induced both mature form of SREBP2 (SREBP2-N) and SREBP2 mRNA induction, which transcriptionally increase NADPH oxidase 2 (Nox2) and NLRP3 expression, thereby leading to IL-1β expression and endothelial inflammation (Figure 1). In this editorial, we will briefly review the NLRP3 inflammasome and SREBP activation system, which play a key role in modulating athero-prone flow-mediated EC inflammation. We will also discuss the following important questions for the future; the role of local NLRP3 and IL-1β expression, mechanisms for two different types of flow (athero-prone flow vs. athero-protective flow) on SREBP2 activation, and other NLRP3 activators including thioredoxin-interacting protein (TXNIP).
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 2
    In: Circulation, 2011, Vol.124(21_MeetingAbstracts Suppl 1)
    ISSN: 0009-7322
    Source: Copyright © 2013 Lippincott Williams & Wilkins. All rights reserved.〈img src=http://exlibris-pub.s3.amazonaws.com/LWW%20logo.png style="vertical-align:middle;margin-left:7px"〉
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  • 3
    In: Circulation, 2010, Vol.122(21_MeetingAbstracts Suppl 1)
    Description: Background: Signal transduction mediated by reactive oxygen species (ROS) such as H2O2 involves control of local generation by oxidases as well as degradation by reductases and scavenging by antioxidants. Recently peroxiredoxinI (PRXI) was shown to control growth factor stimulated local H2O2 production at the plasma membrane. Because PRXI requires thioredoxin (TRX1) for reduction of oxidized proteins the mechanisms that control TRX1 subcellular location will be important. We hypothesized that the scaffold protein TRX1-interacting protein (TXNIP), which binds to TRX1 in a redox-dependent manner would mediate TRX1 plasma membrane function.Methods and Results: Immunofluorescence and cell fractionation studies showed that both TRX1 and TXNIP translocated to the plasma membrane in response to a physiologic level of H2O2 (30 μmol/L, peak= 30min). TRX1 translocation required direct interaction since the non-binding TXNIP-C247S mutant did not cause TRX1 plasma membrane association. H2O2 stimulated a 6-fold increase in tyrosine phosphorylation of membrane-associated proteins that was specific for TRX1 since depletion of glutaredoxin had no effect. VEGFR2 tyrosine phosphorylation was increased 8-fold by H2O2 which was dependent upon TXNIP-TRX1 association with the membrane. VEGFR2 was essential for membrane protein tyrosine phosphorylation and downstream signaling (ERK1/2 and Akt), which were inhibited by TRX1 siRNA, TXNIP siRNA and SU1498. When TXNIP was depleted in endothelial cells by transfection with TXNIP siRNA, apoptosis (23.1 ± 0.8%) was significantly increased compared to cells transfected with control siRNA (8.2 ± 0.6%). Rescue experiments showed that TXNIP binding to TRX1 was required because rescue with TXNIP-C247S did not prevent apoptosis (21.4 ± 0.9%), while rescue with TXNIP-wild-type (WT) prevented cell death (7.5 ± 0.8%).Conclusions: Translocation of TRX1 to the PM by TXNIP is essential for localized VEGFR2 activation and protein phosphorylation.
    ISSN: 0009-7322
    Source: Copyright © 2013 Lippincott Williams & Wilkins. All rights reserved.〈img src=http://exlibris-pub.s3.amazonaws.com/LWW%20logo.png style="vertical-align:middle;margin-left:7px"〉
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  • 4
    In: Circulation, 2012, Vol.126(20), pp.2418-2427
    Description: BACKGROUND—: Carotid intima-media thickening is associated with increased cardiovascular risk in humans. We discovered that intima formation and cell proliferation in response to carotid injury is greater in SJL/J (SJL) in comparison with C3HeB/FeJ (C3H/F) mice. The purpose of this study was to identify candidate genes contributing to intima formation. METHODS AND RESULTS—: We performed microarray and bioinformatic analyses of carotid arteries from C3H/F and SJL mice. Kyoto Encyclopedia of Genes and Genomes analysis showed that the ribosome pathway was significantly up-regulated in C3H/F in comparison with SJL mice. Expression of a ribosomal protein, RpL17, was 〉40-fold higher in C3H/F carotids in comparison with SJL. Aortic vascular smooth muscle cells from C3H/F grew slower in comparison to SJL. To determine the role of RpL17 in vascular smooth muscle cell growth regulation, we analyzed the relationship between RpL17 expression and cell cycle progression. Cultured vascular smooth muscle cells from mice, rats, and humans showed that RpL17 expression inversely correlated with growth as shown by decreased cells in S phase and increased cells in G0/G1. To prove that RpL17 acted as a growth inhibitor in vivo, we used pluronic gel delivery of RpL17 small interfering RNA to C3H/F carotid arteries. This resulted in an 8-fold increase in the number of proliferating cells. Furthermore, following partial carotid ligation in SJL mice, RpL17 expression in the intima and media decreased, but the number of proliferating cells increased. CONCLUSIONS—: RpL17 acts as a vascular smooth muscle cell growth inhibitor (akin to a tumor suppressor) and represents a potential therapeutic target to limit carotid intima-media thickening.
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 5
    In: Circulation, 2011, Vol.124(21_MeetingAbstracts Suppl 1)
    ISSN: 0009-7322
    Source: Copyright © 2013 Lippincott Williams & Wilkins. All rights reserved.〈img src=http://exlibris-pub.s3.amazonaws.com/LWW%20logo.png style="vertical-align:middle;margin-left:7px"〉
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  • 6
    In: Circulation, 2008, Vol.117(8), pp.1082-1089
    Description: Many studies of the human vascular tree have shown that atherosclerosis develops at an early age, with areas of the posterior aorta and branch sites showing the earliest fatty streaks. Closer analysis of the branch points showed that the flow dividers, regions of high shear stress with laminar flow, were relatively protected from fatty streak formation. In contrast, there was a predilection for atherosclerosis at the curvatures and lateral walls of branch points.1 These are regions where disturbed flow occurs; importantly, when the time-averaged shear stress is low, the spatial shear stress gradient is very high.1,2 Both monocyte adhesion and endothelial cell (EC) apoptosis also are highest in these areas.3–6 Recently, Cheng et al7 developed a vascular occluder that induced 3 different regions of altered flow: low, high, and low with oscillatory flow. They observed that lesions always developed in regions of low compared with high shear stress. However, the low shear stress was more likely to develop larger lesions with more lipids, expression of inflammatory mediators, and matrix metalloprotease activity than oscillatory flow. When viewed in concert with a study that showed that regions of low shear stress already had a greater number of inflammatory cells resident in the artery wall as a result of increased trafficking,8 it is clear that low flow is proinflammatory and atherogenic. More sophisticated 3-dimensional analysis of flow patterns in human carotid bifurcations has identified prototypic arterial waveforms, “atheroprone” and “atheroprotective,” representing the wall shear stresses in the carotid sinus, which is susceptible to atherosclerotic lesion development, and the distal internal carotid artery, which is resistant.9 Characteristics of the atheroprone waveform include a high oscillatory shear index (≈0.45) and low time-averaged shear stress amplitude (≈0 dyne/cm2). Thus, both the amplitude and flow pattern are key determinants of …
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 7
    In: Stroke, 2009, Vol.40(2), pp.582-590
    Description: BACKGROUND AND PURPOSE—: Changes in shear and medial wall stress induced by blood flow contribute to vascular remodeling, but details of these relations remain undefined. We hypothesized that remodeling has a strong genetic component and that phenotypic responses to hemodynamic stress will differ among rat strains. Here, we characterized phenotypic traits related to carotid remodeling in the 2 rat strains that we previously showed the greatest difference in shear stress regulation: Genetically Hypertensive (GH) and Brown Norway (BN) rat strains. METHODS—: Left internal and external carotid arteries were ligated and blood flow was reduced in the left common (LCA) by 90% and increased in the right common carotid artery (RCA) by 60%. Rats were studied for up to 28 days after flow modification and carotid outer diameters were measured in vivo, and wall and luminal components by histomorphometry, to obtain indices of remodeling. Blood flow and pressure measurements were made at corresponding time points. RESULTS—: By day 28, remodeling in the GH was greater in response to high flow than in BN, and shear stress was normalized. In contrast, remodeling in the BN was greater in the low flow LCA than in GH. Media stress was greater in GH than BN for any value of carotid shear stress and remained relatively unchanged in low flow, but markedly increased in high flow remodeling. Importantly, pressure was not a major determinant of flow remodeling in these conditions. CONCLUSIONS—: There are key differences in the ability of carotids in GH and BN rats to adhere to hemodynamic laws during vascular remodeling. GH rats exhibit intact regulatory mechanisms for increased, but not reduced, shear stress. Moreover, the ability to maintain physiological shear and media stresses during vascular remodeling in response to modified flow appears to be intrinsically “genetically” determined.
    Keywords: Medicine;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 8
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, 2017, Vol.37(6), pp.1138-1146
    Description: OBJECTIVE—: Oxidative stress and inflammation play key roles in the development of pulmonary arterial hypertension (PAH). Cyclophilin A (CypA) is secreted in response to oxidative stress and promotes inflammation and cardiovascular disease. Endothelial cell (EC) dysfunction is an early event in the pathogenesis of PAH. We evaluated the role of extracellular CypA in PAH and compared the effects of acetylated CypA (AcK-CypA, increased by oxidative stress) and CypA on EC dysfunction. APPROACH AND RESULTS—: In transgenic mice that express high levels of CypA in EC specifically, a PAH phenotype was observed at 3 months including increased right ventricular systolic pressure, α-smooth muscle actin expression in small arterioles, and CD45-positive cells in the lungs. Mechanistic analysis using cultured mouse pulmonary microvascular EC and human pulmonary microvascular EC showed that extracellular CypA and AcK-CypA stimulated EC inflammatory signals: increased VCAM1 (vascular cell adhesion molecule 1) and ICAM1 (intercellular adhesion molecule 1), phosphorylation of p65, and degradation of IkB. Extracellular CypA and AcK-CypA increased EC apoptosis measured by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining, Apo-ONE assay, and caspase 3 cleavage. Oxidative stress stimulated CypA and AcK-CypA secretion, which further promoted EC oxidative stress. AcK-CypA, compared with CypA, stimulated greater increases in apoptosis, inflammation, and oxidative stress. MM284, a specific inhibitor of extracellular CypA, attenuated EC apoptosis induced by CypA and AcK-CypA. CONCLUSIONS—: EC-derived CypA (especially AcK-CypA) causes PAH by a presumptive mechanism involving increased EC apoptosis, inflammation, and oxidative stress. Our results suggest that inhibiting secreted extracellular CypA is a novel therapeutic approach for PAH.
    Keywords: Medicine;
    ISSN: 1079-5642
    E-ISSN: 15244636
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  • 9
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, 2011, Vol.31(8), pp.1890-1897
    Description: OBJECTIVE—: Thioredoxin-interacting protein (TXNIP) promotes inflammation in endothelial cells (EC) by binding to thioredoxin-1 (TRX1) in a redox-dependent manner. Formation of the TXNIP-TRX1 complex relieves inhibition of the apoptosis signal–regulating kinase 1–c-Jun N-terminal kinase–vascular cell adhesion molecule-1 pathway. Because TXNIP is an α-arrestin with numerous protein-protein interacting domains, we hypothesized that TXNIP-TRX1 trafficking should alter function of EC exposed to reactive oxygen species (ROS). METHODS AND RESULTS—: In response to physiological levels of ROS (10 ng/mL tumor necrosis factor-α and 30 μmol/L H2O2), TXNIP-TRX1 translocated to the plasma membrane in human umbilical vein EC, with a peak at 30 minutes, as measured by immunofluorescence colocalization with vascular endothelial-cadherin, cell fractionation, and membrane sheet assay. TXNIP-mediated translocation of TRX1 to the membrane required TXNIP and TRX1 binding, as evidenced by inability of the ROS-insensitive TXNIP-Cys247Ser mutant to promote membrane localization. Vascular endothelial growth factor signaling required TXNIP, as shown by significant decreases in plasma membrane tyrosine phosphorylation and EC migration after TRX1 knockdown. Furthermore, TXNIP knockdown increased human umbilical vein EC apoptosis induced by tumor necrosis factor. Rescue with TXNIP-wild-type but not TXNIP-Cys247Ser prevented cell death. CONCLUSION—: These findings suggest a novel role for the TXNIP-TRX1 complex to enable inflammation by promoting EC survival and vascular endothelial growth factor signaling under conditions of physiological oxidative stress.
    Keywords: Medicine;
    ISSN: 1079-5642
    E-ISSN: 15244636
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  • 10
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, 2018, Vol.38(5), pp.986-993
    Description: CypA (cyclophilin A) is a ubiquitous and highly conserved protein with peptidyl prolyl isomerase activity. Because of its highly abundant level in the cytoplasm, most studies have focused on the roles of CypA as an intracellular protein. However, emerging evidence suggests an important role for extracellular CypA in the pathogenesis of several diseases through receptor (CD147 or other)-mediated autocrine and paracrine signaling pathways. In this review, we will discuss the shared and unique pathological roles of extracellular and intracellular CypA in human cardiovascular diseases. In addition, the evolving role of post-translational modifications of CypA in the pathogenesis of disease is discussed. Finally, recent studies with drugs specific for extracellular CypA show its importance in disease pathogenesis in several animal models and make extracellular CypA a new therapeutic target.
    Keywords: Cardiovascular Diseases ; Cytoplasm ; Endothelial Cells ; Inflammation ; Paracrine Communication;
    ISSN: 1079-5642
    E-ISSN: 15244636
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