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  • 1
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    Online Resource
    Coronary Hemodynamics in Endothelial NO Synthase Knockout Mice
    Ovid Technologies (Wolters Kluwer Health) ; 1998
    In:  Circulation Research Vol. 82, No. 2 ( 1998-02-09), p. 186-194
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 82, No. 2 ( 1998-02-09), p. 186-194
    Abstract: Abstract —For the specific analysis of endothelial NO synthase (eNOS) function in the coronary vasculature, we generated a mouse homozygous for a defective eNOS gene (eNOS−/−). Western blot as well as immunohistochemical staining revealed the absence of eNOS protein in eNOS−/− mice. Aortic endothelial cells derived from eNOS−/− mice displayed only background levels of NO x formation compared with wild-type (WT) cells (88 versus 1990 pmol NO x · h −1 /mg protein −1 ). eNOS−/− mice were hypertensive (mean arterial pressure, 135±15 versus 107±8 mm Hg in WT) without the development of cardiac hypertrophy. Coronary hemodynamics, analyzed in Langendorff-perfused hearts, showed no differences either in basal coronary flow or in maximal and repayment flow of reactive hyperemia. Acute NOS inhibition with N ω -nitro- l -arginine methyl ester (L-NAME) in WT hearts substantially reduced basal flow and reactive hyperemia. The coronary response to acetylcholine (ACh) (500 nmol/L) was biphasic: An initial vasoconstriction (flow, −35%) in WT hearts was followed by sustained vasodilation (+190%). L-NAME significantly reduced vasodilation in WT hearts (+125%) but did not alter the initial vasoconstriction. In eNOS−/− hearts, the initial vasoconstriction was augmented (−70%), whereas the ACh-induced vasodilation was not affected. Inhibition of cyclooxygenase with diclofenac converted the ACh-induced vasodilation into vasoconstriction (−49% decrease of basal flow). This effect was even more pronounced in eNOS−/− hearts (−71%). Our results demonstrate that (1) acute inhibition of eNOS reveals a role for NO in setting the basal coronary vascular tone as well as participation in reactive hyperemia and the response to ACh; (2) chronic inhibition of NO formation in eNOS−/− mutant mice induces no changes in basal coronary flow and reactive hyperemia, suggesting the activation of important compensatory mechanisms; and (3) prostaglandins are the main mediators of the ACh-induced vasodilation in both WT and eNOS−/− mice.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.82.2.186
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1998
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  • 2
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    The Janus Faces of NO?
    Ovid Technologies (Wolters Kluwer Health) ; 2004
    In:  Circulation Research Vol. 94, No. 6 ( 2004-04-02)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 94, No. 6 ( 2004-04-02)
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.0000124241.01300.A3
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2004
    detail.hit.zdb_id: 80100-8
    detail.hit.zdb_id: 1467838-X
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  • 3
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    Cardiac hypertrophy in myoglobin knockout mice in vivo
    Wiley ; 2007
    In:  The FASEB Journal Vol. 21, No. 5 ( 2007-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 21, No. 5 ( 2007-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v21.5
    DOI: 10.1096/fasebj.21.5.A263-b
    Language: English
    Publisher: Wiley
    Publication Date: 2007
    detail.hit.zdb_id: 1468876-1
    detail.hit.zdb_id: 639186-2
    SSG: 12
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  • 4
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    IGF1‐receptor signalling modulates diastolic cardiac function in aging hearts
    Wiley ; 2012
    In:  The FASEB Journal Vol. 26, No. S1 ( 2012-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 26, No. S1 ( 2012-04)
    Abstract: Insulin‐like growth factor receptor (IGF1R) signalling appears to play an important role in cardiac growth, contractile function, and the development of age related congestive heart failure. Here we address the question to what extent cardiomyocyte specific IGF1R signalling is essential for maintenance of the structural and functional integrity of the adult murine heart. We inactivated the IGF1R by a 4‐OHTX inducible Cre recombinase in cardiac myocytes of adult mice. Western blots and RT‐PCR demonstrated efficient inactivation of the IGF1R (iCMIGF1RKO)associated with reduced AKT and GSK3β‐phosphorylation. In adult iCMIGF1RKO mice(age 3 month)assessment of cardiac function by P/V catheter and MRI revealed no functional alterations. When the KO was induced in aged mice (11 month) diastolic cardiac function was more depressed in iCMIGF1RKO mice. To test if insulin signalling compensated for the loss of IGF1R, we inactivated β‐cells by STZ. The diabetes associated functional depression was similar in WT and iCMIGF1RKO mice. Analysis of the cardiac transcriptome on 44K microarrays did not reveal activation of overt adaptive processes. Conclusion Endogenous IGF1 receptor signalling is required for conservation of cardiac function of the aging but not the young heart.
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v26.S1
    DOI: 10.1096/fasebj.26.1_supplement.974.4
    Language: English
    Publisher: Wiley
    Publication Date: 2012
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    detail.hit.zdb_id: 639186-2
    SSG: 12
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  • 5
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    Enhanced Blood Pressure Variability in eNOS Knockout Mice
    Ovid Technologies (Wolters Kluwer Health) ; 1999
    In:  Hypertension Vol. 33, No. 6 ( 1999-06), p. 1359-1363
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. 6 ( 1999-06), p. 1359-1363
    Abstract: Abstract —It has been shown previously that endogenous nitric oxide can buffer arterial blood pressure variability in dogs and rats. In these former studies, all isoforms of the nitric oxide synthase were blocked pharmacologically and an increased blood pressure variability was observed. Thus the question as to which isoform of the nitric oxide synthase is responsible for the blood pressure buffering effect of endogenous nitric oxide remains unraveled. In the present study, we therefore compared blood pressure variability in knockout mice that lack specifically the gene for endothelial nitric oxide synthase with their respective wild-type controls. One day after carotid artery cannulation, blood pressure was recorded in these conscious mice. During resting conditions, blood pressure variability was markedly enhanced in knockout mice compared with wild-type mice (10.5±1.5 mm Hg 2 vs 6.0±0.8 mm Hg 2 , P 〈 0.05). Power spectral analysis revealed that this increase in blood pressure variability is manifested at low frequencies that range from 0.05 to 0.40 s −1 (Hz) (5.1±1.0 mm Hg 2 vs 2.5±0.5 mm Hg 2 , P 〈 0.05). On the basis of these results, we conclude that the blood pressure buffering effect of endogenous nitric oxide is mediated by the endothelial isoform of the nitric oxide synthase. In addition, endothelial nitric oxide is most effective in buffering blood pressure oscillations at frequencies that range from 0.05 to 0.40 s −1 (Hz) in conscious mice.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/01.HYP.33.6.1359
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1999
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  • 6
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    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: 80100-8
    detail.hit.zdb_id: 1467838-X
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  • 7
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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
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  • 8
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    Defective Bone Formation and Anabolic Response to Exogenous Estrogen in Mice with Targeted Disruption of Endothelial Nitric Oxide Synthase**This study was supported by grants from the Arthritis Research Campaign (UK) and the Medical Research Council (UK).
    The Endocrine Society ; 2001
    In:  Endocrinology Vol. 142, No. 2 ( 2001-02-01), p. 760-766
    Details
    In: Endocrinology, The Endocrine Society, Vol. 142, No. 2 ( 2001-02-01), p. 760-766
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    URL: Article
    DOI: 10.1210/endo.142.2.7977
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2001
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    detail.hit.zdb_id: 2011695-0
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  • 9
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    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: 80100-8
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  • 10
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    Abstract 484: Nitrosative Stress Enhances S-nitrosation Of Peroxiredoxins In The Heart
    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: Nitric oxide (NO) is produced by different isoforms of NO-synthases and operates as a mediator of important cell signaling pathways. To explore thiol-based protein modifications in a situation of nitrosative stress, two transgenic mouse models recently generated in our laboratory were used: Cardiac specific overexpression of inducible nitric oxide synthase (iNOS) (tg-iNOS + ) and tg-iNOS + with concomitant myoglobin-deficiency (tg-iNOS + /myo −/− ). Protein S-nitrosation, an important redox-based posttranslational modification, revealed no differences between WT and tg-iNOS + hearts as measured by the biotin-switch assay and 2-D PAGE. Even in the absence of myoglobin - an efficient endogenous NO-oxidase - the protein S-nitrosation pattern for nearly all the detected proteins ( 〉 40) remained unchanged in the tg-iNOS + /myo −/− hearts, with the exception of three proteins. Tandem mass spectrometry uncovered these proteins as peroxiredoxins (Prx II, III, VI), which are known to possess peroxidase activity, whereby hydrogen peroxide, peroxynitrite and a wide range of organic hydroperoxides are reduced and detoxified. To prove whether the higher abundance of the Prxs was due to enhanced S-nitrosation or due to changes in their basal expression levels, immunoblotting with specific antibodies was applied and revealed upregulation of Prx VI in tg-iNOS + /myo −/− hearts. The other proteins found to be S-nitrosated were identified as well. Data mining indicated a significant overlap of these proteins with proteins becoming glutathiolated. Protein glutathiolation detected by immunoblotting was enhanced in the tg-iNOS + hearts and even more so in the tg-iNOS + /myo −/− hearts. We conclude that protein glutathiolation in our transgenic model of nitrosative stress is important to protect protein thiols from irreversible oxidation. The upregulation of antioxidant proteins like Prx VI appears to be an additional mechanism to antagonize an excess of reactive oxygen/nitrogen species. Enhanced S-nitrosation of the Prxs may serve a new function in the signalling cascade coping with nitrosative stress.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.116.suppl_16.II_82-c
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 1466401-X
    detail.hit.zdb_id: 80099-5
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