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  • 1
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    Online Resource
    The Osmolyte Taurine Protects against Ultraviolet B Radiation-Induced Immunosuppression
    The American Association of Immunologists ; 2007
    In:  The Journal of Immunology Vol. 179, No. 6 ( 2007-09-15), p. 3604-3612
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 179, No. 6 ( 2007-09-15), p. 3604-3612
    Abstract: Organic osmolytes, such as taurine, are involved in cell volume homeostasis and cell protection. Epidermal keratinocytes possess an osmolyte strategy, i.e., they take up taurine upon hyperosmotic stress and express the corresponding transporter TAUT. UVB irradiation also triggers taurine uptake and TAUT expression in this cell type. We therefore asked whether taurine plays a role in photoprotection. By using a TAUT-deficient mouse model, lack of taurine in the skin was found to cause a significantly higher sensitivity to UVB-induced immunosuppression. This was not due to an increased generation or decreased repair of UVB-induced DNA photoproducts in the skin of these animals. Instead, decreased skin taurine levels were associated with an increased formation of the soluble immunosuppressive molecule platelet-activating factor (PAF) from the membranes of UVB-irradiated epidermal cells. Blocking PAF activity in taut-deficient mice with a PAF receptor antagonist abrogated their increased sensitivity to UVB-induced immunosuppression. Moreover, taut −/− mice were more sensitive to PAF-mediated immunosuppression than taut +/+ mice. These data suggest that taurine uptake by epidermal cells prevents undue PAF formation, and thereby photoimmunosuppression. Thus, similar to nucleotide excision repair, taurine uptake is critically involved in photoprotection of the skin.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.179.6.3604
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2007
    detail.hit.zdb_id: 1475085-5
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  • 2
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    Targeted Disruption of cd73 /Ecto-5′-Nucleotidase Alters Thromboregulation and Augments Vascular Inflammatory Response
    Ovid Technologies (Wolters Kluwer Health) ; 2004
    In:  Circulation Research Vol. 95, No. 8 ( 2004-10-15), p. 814-821
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 95, No. 8 ( 2004-10-15), p. 814-821
    Abstract: To investigate the role of adenosine formed extracellularly in vascular homeostasis, mice with a targeted deletion of the cd73 /ecto-5′-nucleotidase were generated. Southern blot, RT-PCR, and Western blot analysis confirmed the constitutive knockout. In vivo analysis of hemodynamic parameters revealed no significant differences in systolic blood pressure, ejection fraction, or cardiac output between strains. However, basal coronary flow measured in the isolated perfused heart was significantly lower (−14%; P 〈 0.05) in the mutant. Immunohistochemistry revealed strong CD73 expression on the endothelium of conduit vessels in wild-type (WT) mice. Time to carotid artery occlusion after ferric chloride (FeCl 3 ) was significantly reduced by 20% in cd73 −/− mice ( P 〈 0.05). Bleeding time after tail tip resection tended to be shorter in cd73 −/− mice (−35%). In vivo platelet cAMP levels were 0.96±0.46 in WT versus 0.68±0.27 pmol/10 6 cells in cd73 −/− mice ( P 〈 0.05). Under in vitro conditions, platelet aggregation in response to ADP (0.05 to 10 μmol/L) was undistinguishable between the two strains. In the cremaster model of ischemia–reperfusion, the increase in leukocyte attachment to endothelium was significantly higher in cd73 −/− compared with WT littermates (WT 98% versus cd73 −/− 245%; P 〈 0.005). The constitutive adhesion of monocytes in ex vivo–perfused carotid arteries of WT mice was negligible but significantly increased in arteries of cd73 −/− mice ( P 〈 0.05). Thus, our data provide the first evidence that adenosine, extracellularly formed by CD73, can modulate coronary vascular tone, inhibit platelet activation, and play an important role in leukocyte adhesion to the vascular endothelium in vivo.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.0000144796.82787.6f
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2004
    detail.hit.zdb_id: 1467838-X
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  • 3
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    Online Resource
    Cardiac-Specific Overexpression of Inducible Nitric Oxide Synthase Does Not Result in Severe Cardiac Dysfunction
    Ovid Technologies (Wolters Kluwer Health) ; 2002
    In:  Circulation Research Vol. 90, No. 1 ( 2002-01-11), p. 93-99
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 90, No. 1 ( 2002-01-11), p. 93-99
    Abstract: Nitric oxide (NO), a potent regulator of myocardial contractility, has been implicated in the development of heart failure; however, no study exists describing the relation between expression of inducible nitric oxide synthase (iNOS), formation of NO in vivo, and cardiac contractility. We have therefore generated transgenic (TG) mice overexpressing iNOS under the cardiospecific α-myosin heavy chain (α-MHC) promoter. In vitro, iNOS activity in hearts of two transgenic lines was 260- to 400-fold above controls (wild type [WT]), but TG mice were viable and appeared normal. Ventricular mass/body weight ratio did not differ; heart rate and cardiac output as well as mean arterial blood pressure were decreased by 10%. NO x levels of hearts and blood of TG mice were 2.5- and 2-fold above WT controls, respectively. In the isolated heart, release of the NO oxidation products nitrate and nitrite, an index of in vivo NOS activity, was 40-fold over WT. However, cardiac hemodynamics and levels of ATP and phosphocreatine were unaltered. The high iNOS activity was associated with reduced cardiac l -arginine in TG hearts to only 15% of the WT, indicating limited substrate availability, whereas l -citrulline was 20-fold elevated. Our findings demonstrate that the heart can tolerate high levels of iNOS activity without detrimental functional consequences. The concept that iNOS-derived NO is the triggering factor in the pathomechanism leading to heart failure therefore needs to be reevaluated.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/hh0102.102757
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2002
    detail.hit.zdb_id: 1467838-X
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  • 4
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    Abstract 2243: In Vivo 3D MR Angiography Reveals Accelerated Collateral Vessel Growth in CD73 −/− Mice after Hindlimb Ischemia
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Vol. 118, No. suppl_18 ( 2008-10-28)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 118, No. suppl_18 ( 2008-10-28)
    Abstract: Adenosine is a potent stimulator of angiogenesis, however, its role in arteriogenesis is not yet known. To address this issue we induced severe hindlimb ischemia in a mouse mutant lacking CD73 (ecto-5′-nucleotidase) which shows enhanced monocyte adhesion to the endothelium, considered to be an important initial trigger for arteriogenesis. For serial comparison of blood flow recovery and direct visualization of newly developed collateral vessels in wild-type (WT) and CD73 −/− mice we established a high resolution 3D MR angiography (MRA) protocol. MRA images (field of view 2.56x2.56x1.92 cm 3 , matrix 256x256x192, voxel size 1 nl) of murine hindlimbs were recorded at 9.4 T within a reasonable acquisition time of approximately 30 min and were subsequently segmented and quantified using in-house-developed software. Collateral flow was detected as early as 3 d after ligation reaching a transient maximum 7 d after occlusion. At this time the extent of collateralization in the ischemic area was substantially enlarged in CD73 −/− mice (+70% vs. WT, p 〈 0.05, n=6). The improved blood supply was also reflected in a faster recovery of hindlimb muscle energetics in the mutant compared with WT controls as assessed by 31 P MR spectroscopy in vivo . Histology confirmed the enhanced development of collaterals in CD73 −/− mice. In conclusion, our protocol allows the quantitative assessment of growing collateral vessels in mice. We found that lack of CD73-derived adenosine promotes arteriogenesis. Fig. 1 : MRA from hindlimbs of CD73 −/− mice 7 d after ligation of the femoral artery. Newly developed collateral vessels are colored in green. Insert shows the typical “corkscrew morphology” of the collaterals.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.118.suppl_18.S_692-b
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 1466401-X
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  • 5
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    Linsitinib, AN IGF-1R inhibitor, attenuates disease development and progression in a model of thyroid eye disease
    Bioscientifica ; 2023
    In:  Endocrine Abstracts ( 2023-08-24)
    Details
    In: Endocrine Abstracts, Bioscientifica, ( 2023-08-24)
    Type of Medium: Online Resource
    ISSN: 1479-6848
    URL: Article
    DOI: 10.1530/endoabs.92.OP-09-03
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2023
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  • 6
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    Lack of Myoglobin Causes a Switch in Cardiac Substrate Selection
    Ovid Technologies (Wolters Kluwer Health) ; 2005
    In:  Circulation Research Vol. 96, No. 8 ( 2005-04-29)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 96, No. 8 ( 2005-04-29)
    Abstract: Myoglobin is an important intracellular O 2 binding hemoprotein in heart and skeletal muscle. Surprisingly, disruption of myoglobin in mice (myo −/− ) resulted in no obvious phenotype and normal cardiac function was suggested to be mediated by structural alterations that tend to steepen the oxygen pressure gradient from capillary to mitochondria. Here we report that lack of myoglobin causes a biochemical shift in cardiac substrate utilization from fatty acid to glucose oxidation. Proteome and gene expression analysis uncovered key enzymes of mitochondrial β-oxidation as well as the nuclear receptor PPARα to be downregulated in myoglobin-deficient hearts. Using FDG-PET we showed a substantially increased in vivo cardiac uptake of glucose in myo −/− mice (6.7±2.3 versus 0.8±0.5% of injected dose in wild-type, n=5, P 〈 0.001), which was associated with an upregulation of the glucose transporter GLUT4. The metabolic switch was confirmed by 13 C NMR spetroscopic isotopomer studies of isolated hearts which revealed that [1,6- 13 C 2 ]glucose utilization was increased in myo −/− hearts (38±8% versus 22±5% in wild-type, n=6, P 〈 0.05), and concomitantly, [U- 13 C 16 ]palmitate utilization was decreased in the myoglobin-deficient group (42±6% versus 63±11% in wild-type, n=6, P 〈 0.05). Because of the O 2 -sparing effect of glucose utilization, the observed shift in substrate metabolism benefits energy homoeostasis and therefore represents a molecular adaptation process allowing to compensate for lack of the cytosolic oxygen carrier myoglobin. Furthermore, our data suggest that an altered myoglobin level itself may be a critical determinant for substrate selection in the heart. The full text of this article is available online at http://circres.ahajournals.org.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.0000165481.36288.d2
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2005
    detail.hit.zdb_id: 1467838-X
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  • 7
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    Abstract 1910: Monitoring of Inflammatory Processes By In Vivo 19F Magnetic Resonance Imaging
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Circulation Vol. 116, No. suppl_16 ( 2007-10-16)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. suppl_16 ( 2007-10-16)
    Abstract: This study was aimed at developing a new approach for in vivo detection of inflammation by 19 F magnetic resonance imaging (MRI) using biochemically inert emulsified perfluorocarbons (PFCs). PFCs have been clinically used as blood substitutes and are known to be phagocytized by the reticuloendothelial system. Local inflammation was provoked in two murine models of acute cardiac and cerebral ischemia, respectively, followed by intravenous injection of PFCs. A typical example of anatomically matching 1 H and 19 F images obtained at 9.4 Tesla 4 days after myocardial infarction is shown below. The 1 H image (left) clearly shows the presence of ventricular dilatation and wall thinning within the infarcted area (I), and in the corresponding 19 F image (middle) a signal pattern matched in shape of the free left ventricular wall. Merging of these images (right) confirms the localization of PFCs within the anterior, lateral, and posterior wall. In all animals (n=8) studied, 19 F signal was also detected in the adjacent chest tissue, where thoracotomy for infarction was performed (T). No background signal from other tissue was observed. Repetitive MRI revealed in both injury models a time-dependent infiltration of injected PFCs into infarcted areas, and histology demonstrated a colocalization of PFCs with cells of the monocyte-macrophage system. Using rhodamine-labelled PFCs, circulating monocytes/macrophages were identified to be the main cell fraction taking up injected PFCs. In conclusion, PFCs can serve as positive contrast agent for detection of inflammatory processes by MRI, permitting high spatial resolution and an excellent degree of specificity due to lack of any 19 F background.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.116.suppl_16.II_410-c
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 1466401-X
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  • 8
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    Online Resource
    Acute Inhibition of Myoglobin Impairs Contractility and Energy State of iNOS-Overexpressing Hearts
    Ovid Technologies (Wolters Kluwer Health) ; 2003
    In:  Circulation Research Vol. 92, No. 12 ( 2003-06-27), p. 1352-1358
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 92, No. 12 ( 2003-06-27), p. 1352-1358
    Abstract: Elevated cardiac levels of nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) have been implicated in the development of heart failure. The surprisingly benign phenotype of recently generated mice with cardiac-specific iNOS overexpression (TGiNOS) provided the rationale to investigate whether NO scavenging by oxymyoglobin (MbO 2 ) yielding nitrate and metmyoglobin (metMb) is involved in preservation of myocardial function in TGiNOS mice. 1 H nuclear magnetic resonance (NMR) spectroscopy was used to monitor changes of cardiac myoglobin (Mb) metabolism in isolated hearts of wild-type (WT) and TGiNOS mice. NO formation by iNOS resulted in a significant decrease of the MbO 2 signal and a concomitantly emerging metMb signal in spectra of TGiNOS hearts only (ΔMbO 2 : −46.3±38.4 μmol/kg, ΔmetMb: +41.4±17.6 μmol/kg, n=6; P 〈 0.05) leaving contractility and energetics unaffected. Inhibition of the Mb-mediated NO degradation by carbon monoxide (20%) led to a deterioration of myocardial contractility in TGiNOS hearts (left ventricular developed pressure: 78.2±8.2% versus 96.7±4.6% of baseline, n=6; P 〈 0.005), which was associated with a profound pertubation of cardiac energy state as assessed by 31 P NMR spectroscopy (eg, phosphocreatine: 13.3±1.3 mmol/L (TGiNOS) versus 15.9±0.7 mmol/L (WT), n=6; P 〈 0.005). These alterations could be fully antagonized by the NOS inhibitor S -ethylisothiourea. Our findings demonstrate that myoglobin serves as an important cytoplasmic buffer of iNOS-derived NO, which determines the functional consequences of iNOS overexpression.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.0000079026.70629.E5
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2003
    detail.hit.zdb_id: 1467838-X
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  • 9
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    Online Resource
    Nitrite Reductase Function of Deoxymyoglobin : Oxygen Sensor and Regulator of Cardiac Energetics and Function
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Circulation Research Vol. 100, No. 12 ( 2007-06-22), p. 1749-1754
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 100, No. 12 ( 2007-06-22), p. 1749-1754
    Abstract: Although the primary function of myoglobin (Mb) has been considered to be cellular oxygen storage and supply, recent studies have suggested to classify Mb as a multifunctional allosteric enzyme. In the heart, Mb acts as a potent scavenger of nitric oxide (NO) and contributes to the attenuation of oxidative damage. Here we report that a dynamic cycle exists in which a decrease in tissue oxygen tension drives the conversion of Mb from being an NO scavenger in normoxia to an NO producer in hypoxia. The NO generated by reaction of deoxygenated Mb with nitrite is functionally relevant and leads to a downregulation of cardiac energy status, which was not observed in mice lacking Mb. As a consequence, myocardial oxygen consumption is reduced and cardiac contractility is dampened in wild-type mice. We propose that this pathway represents a novel homeostatic mechanism by which a mismatch between oxygen supply and demand in muscle is translated into the fractional increase of deoxygenated Mb exhibiting enhanced nitrite reductase activity. Thus, Mb may act as an oxygen sensor which through NO can adjust muscle energetics to limited oxygen supply.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.107.152488
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 1467838-X
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  • 10
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    Online Resource
    Early Assessment of Pulmonary Inflammation by 19 F MRI In Vivo
    Ovid Technologies (Wolters Kluwer Health) ; 2010
    In:  Circulation: Cardiovascular Imaging Vol. 3, No. 2 ( 2010-03), p. 202-210
    Details
    In: Circulation: Cardiovascular Imaging, Ovid Technologies (Wolters Kluwer Health), Vol. 3, No. 2 ( 2010-03), p. 202-210
    Abstract: Background— Emulsified perfluorocarbons (PFCs) are preferentially phagocytized by monocytes/macrophages and are readily detected by 19 F MRI. This study tests the hypothesis that 19 F MRI can be used to quantitate pulmonary inflammation by tracking of infiltrating PFC-loaded monocytes. Methods and Results— Pneumonia was induced in mice by intratracheal instillation of lipopolysaccharides (LPS) followed by intravenous injection of PFCs. Whereas regular 1 H MRI provided no evidence of lung injury 24 hours after LPS, the concurrent 19 F images clearly show PFC accumulation in both pulmonary lobes. Imaging at 48 hours after LPS revealed signals in 1 H images at the same location as the 24-hour 19 F signals. Thus, progressive pneumonia was first predicted by 19 F MRI early after PFC administration. Without LPS, at no time were 19 F signals observed within the lung. Histology and fluorescence-activated cell sorting (FACS) combined with 19 F MRI confirmed the presence of infiltrating PFC-loaded monocytes/macrophages after LPS challenge. Additional experiments with graded doses of LPS demonstrated that 19 F signal intensity strongly correlated with both LPS dose and pathological markers of lung inflammation. In separate studies, dexamethasone and CGS21680 (adenosine 2A receptor agonist) were used to demonstrate the ability of 19 F MRI to monitor anti-inflammatory therapies. Conclusions— PFCs serve as a contrast agent for the prognostic and quantitative assessment of pulmonary inflammation by in vivo 19 F MRI, which is characterized by a high degree of specificity due to the lack of any 19 F background. Because PFCs are biochemically inert, this approach may also be suitable for human applications.
    Type of Medium: Online Resource
    ISSN: 1941-9651 , 1942-0080
    URL: Article
    DOI: 10.1161/CIRCIMAGING.109.902312
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2010
    detail.hit.zdb_id: 2440475-5
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