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  • 1
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    Renin Inhibition Improves Cardiac Function and Remodeling After Myocardial Infarction Independent of Blood Pressure
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Hypertension Vol. 52, No. 6 ( 2008-12), p. 1068-1075
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 52, No. 6 ( 2008-12), p. 1068-1075
    Kurzfassung: Pharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure–lowering effects. We investigated the effect of aliskiren on cardiac remodeling, apoptosis, and left ventricular (LV) function after experimental myocardial infarction (MI). C57J/bl6 mice were subjected to coronary artery ligation and were treated for 10 days with vehicle or aliskiren (50 mg/kg per day via an SC osmopump), whereas sham-operated animals served as controls. This dose of aliskiren, which did not affect systemic blood pressure, improved systolic and diastolic LV function, as measured by the assessment of pressure-volume loops after MI. Furthermore, after MI LV dilatation, cardiac hypertrophy and lung weights were decreased in mice treated with aliskiren compared with placebo-treated mice after MI. This was associated with a normalization of the mitogen-activated protein kinase P38 and extracellular signal-regulated kinases 1/2, AKT, and the apoptotic markers bax and bcl-2 (all measured by Western blots), as well as the number of TUNEL-positive cells in histology. LV dilatation, as well as the associated upregulation of gene expression (mRNA abundance) and activity (by zymography) of the cardiac metalloproteinase 9 in the placebo group after MI, was also attenuated in the aliskiren-treated group. Aliskiren improved LV dysfunction after MI in a dose that did not affect blood pressure. This was associated with the amelioration of cardiac remodelling, hypertrophy, and apoptosis.
    Materialart: Online-Ressource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.108.116350
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2008
    ZDB Id: 2094210-2
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
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    Reduced Degradation of the Chemokine MCP-3 by Matrix Metalloproteinase-2 Exacerbates Myocardial Inflammation in Experimental Viral Cardiomyopathy
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Vol. 124, No. 19 ( 2011-11-08), p. 2082-2093
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 124, No. 19 ( 2011-11-08), p. 2082-2093
    Kurzfassung: Myocarditis is an important cause for cardiac failure, especially in younger patients, followed by the development of cardiac dysfunction and death. The present study investigated whether gene deletion of matrix metalloproteinase-2 influences cardiac inflammation and function in murine coxsackievirus B3 (CVB3)–induced myocarditis. Methods and Results— Matrix metalloproteinase-2 knockout mice (MMP-2 −/− ) and their wild-type controls (WT) were infected with CVB3 to induce myocarditis. Three days after infection, an increased invasion of CD4 + -activated T cells into the myocardium was documented, followed by an excess of inflammatory cells 7 days after infection, which was significantly higher in the MMP-2 −/− animals compared with the WT animals. Moreover, cardiac apoptosis, remodeling, viral load, and function were deteriorated in MMP-2 −/− animals after CVB3 infection. This overwhelming inflammation was followed by 100% mortality after 15 days. This was associated with increased levels of MCP-3 in the cardiac tissue of MMP-2 −/− mice. Because MMP-2 cleaves the chemokine MCP-3, the loss of this cleavage lead to an overreaction of the immune system with pronounced myocardial damage mediated by the inflammatory cells. When a neutralizing antibody against MCP-3 was given to MMP-2 −/− mice, this exaggerated reaction of the immune system could be normalized to levels similar to WT-CVB3 animals. Conclusions— Loss of MMP-2 increased the inflammatory response after CVB3 infection, which impaired cardiac function and survival during CVB3-induced myocarditis. Matrix metalloproteinase-2–mediated chemokine cleavage has an important role in cardiac inflammation as a negative feedback mechanism.
    Materialart: Online-Ressource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.111.035964
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2011
    ZDB Id: 1466401-X
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    Myeloid differentiation factor-88 contributes to TLR9-mediated modulation of acute coxsackievirus B3-induced myocarditis in vivo
    American Physiological Society ; 2010
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 298, No. 6 ( 2010-06), p. H2024-H2031
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 298, No. 6 ( 2010-06), p. H2024-H2031
    Kurzfassung: Toll-like receptor 9 (TLR9) is a member of the innate immune system and has been shown to influence myocardial function, but its role in myocarditis is hitherto unknown. We therefore investigated whether or not TLR9 plays a role in this disease in coxsackievirus B3 (CVB3)-induced myocarditis in mice. Left ventricular (LV) function, cardiac immune cell infiltration, virus mRNA, and components of the TLR9 downstream pathway were investigated in TLR9-deficient [knockout (KO)] and wild-type (WT) mice after infection with CVB3. Murine cardiac TLR9 expression was significantly increased in WT mice with acute CVB3 infection but not in WT mice with chronic myocarditis. Furthermore, in the acute phase of CVB3-induced myocarditis, CVB3-infected KO mice displayed improved LV function associated with reduced cardiac inflammation indexed by reduced amounts of immune cells compared with CVB3-infected WT mice. In contrast, in the chronic phase, LV function and inflammation were not seen to differ among the infected groups. The cardioprotective effects due to TLR9 deficiency were associated with suppression of the TLR9 downstream pathway as indexed by reduced cardiac levels of the adapter protein myeloid differentiation factor (MyD)-88 and the proinflammatory cytokine TNF-α. In addition, TLR9 deficiency led to an activation of the antiviral cytokine interferon-β in the heart as a result from viral infection. In conclusion, the MyD88/TNF-α axis due to TLR9 activation in the heart contributes the development of acute myocarditis but not of chronic myocarditis.
    Materialart: Online-Ressource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.01188.2009
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: American Physiological Society
    Publikationsdatum: 2010
    ZDB Id: 1477308-9
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
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    Doxorubicin cardiomyopathy-induced inflammation and apoptosis are attenuated by gene deletion of the kinin B1 receptor
    Walter de Gruyter GmbH ; 2008
    In:  bchm Vol. 389, No. 6 ( 2008-06-01), p. 713-718
    Details
    In: bchm, Walter de Gruyter GmbH, Vol. 389, No. 6 ( 2008-06-01), p. 713-718
    Kurzfassung: Clinical use of the anthracycline doxorubicin (DOX) is limited by its cardiotoxic effects, which are attributed to the induction of apoptosis. To elucidate the possible role of the kinin B1 receptor (B1R) during the development of DOX cardiomyopathy, we studied B1R knockout mice (B1R -/- ) by investigating cardiac inflammation and apoptosis after induction of DOX-induced cardiomyopathy. DOX control mice showed cardiac dysfunction measured by pressure-volume loops in vivo . This was associated with a reduced activation state of AKT, as well as an increased bax/bcl2 ratio in Western blots, indicating cardiac apoptosis. Furthermore, mRNA levels of the proinflammatory cytokine interleukin 6 were increased in the cardiac tissue. In DOX B1R -/- mice, cardiac dysfunction was improved compared to DOX control mice, which was associated with normalization of the bax/bcl-2 ratio and interleukin 6, as well as AKT activation state. These findings suggest that B1R is detrimental in DOX cardiomyopathy in that it mediates the inflammatory response and apoptosis. These insights might have useful implications for future studies utilizing B1R antagonists for treatment of human DOX cardiomyopathy.
    Materialart: Online-Ressource
    ISSN: 1437-4315 , 1431-6730
    URL: Article
    DOI: 10.1515/BC.2008.070
    Sprache: Englisch
    Verlag: Walter de Gruyter GmbH
    Publikationsdatum: 2008
    ZDB Id: 1466062-3
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Cardiac Inflammation Contributes to Changes in the Extracellular Matrix in Patients With Heart Failure and Normal Ejection Fraction
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation: Heart Failure Vol. 4, No. 1 ( 2011-01), p. 44-52
    Details
    In: Circulation: Heart Failure, Ovid Technologies (Wolters Kluwer Health), Vol. 4, No. 1 ( 2011-01), p. 44-52
    Kurzfassung: The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF. Methods and Results— We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-β. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-β, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-β resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction. Conclusions— Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM.
    Materialart: Online-Ressource
    ISSN: 1941-3289 , 1941-3297
    URL: Article
    DOI: 10.1161/CIRCHEARTFAILURE.109.931451
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2011
    ZDB Id: 2428100-1
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
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    Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 2 ( 2009-01-15), p. 695-699
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 2 ( 2009-01-15), p. 695-699
    Kurzfassung: Cardiotoxicity, which may result from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anticancer therapy using doxorubicin. Because statins might exert beneficial pleiotropic cardiovascular effects, among other things, by anti-inflammatory and antioxidative mechanisms, we investigated whether or not fluvastatin pretreatment can attenuate doxorubicin-induced cardiotoxicity. Five days after a single injection of doxorubicin (20 mg/kg; i.p.), left ventricular (LV) function was measured in fluvastatin-treated (DoxStatin; 100 mg/kg/day, p.o.) and saline-treated (doxorubicin) mice (n = 8 per group) by a micro conductance catheter. Untreated mice served as controls (placebo; n = 8 per group). After measurement of cardiac function, LV tissues were analyzed by molecular biological and immunohistologic methods. Injection resulted in significantly impaired LV function (LV pressure, −29%; dp/dtmax, −45%; cardiac output, −68%; P & lt; 0.05) when compared with placebo. This was associated with a significant increase in cardiac oxidative stress, inflammation and apoptotic mechanisms, as indicated by significant increased cardiac lipid peroxidation activity, protein expression of nitrotyrosine, tumor necrosis factor α and Bax (P & lt; 0.05). In contrast, DoxStatin mice showed improved LV function (LV pressure, +24%; dp/dtmax, +87%; cardiac output, +87%; P & lt; 0.05) when compared with untreated doxorubicin mice. This was associated with reduced cardiac expression of nitrotyrosine, enhanced expression of the mitochondrial located antioxidative SOD 2, attenuated mitochondrial apoptotic pathways, and reduced cardiac inflammatory response. Statin pretreatment attenuates doxorubicin-induced cardiotoxicity via antioxidative and anti-inflammatory effects. [Cancer Res 2009;69(2):695–9]
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-3076
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2009
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    Online-Ressource
    Gene Deletion of the Kinin Receptor B1 Attenuates Cardiac Inflammation and Fibrosis During the Development of Experimental Diabetic Cardiomyopathy
    American Diabetes Association ; 2009
    In:  Diabetes Vol. 58, No. 6 ( 2009-06-01), p. 1373-1381
    Details
    In: Diabetes, American Diabetes Association, Vol. 58, No. 6 ( 2009-06-01), p. 1373-1381
    Kurzfassung: Diabetic cardiomyopathy is associated with increased mortality in patients with diabetes. The underlying pathology of this disease is still under discussion. We studied the role of the kinin B1 receptor on the development of experimental diabetic cardiomyopathy. RESEARCH DESIGN AND METHODS We utilized B1 receptor knockout mice and investigated cardiac inflammation, fibrosis, and oxidative stress after induction of streptozotocin (STZ)-induced diabetes. Furthermore, the left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes. RESULTS B1 receptor knockout mice showed an attenuation of diabetic cardiomyopathy with improved systolic and diastolic function in comparison with diabetic control mice. This was associated with a decreased activation state of the mitogen-activated protein kinase p38, less oxidative stress, as well as normalized cardiac inflammation, shown by fewer invading cells and no increase in matrix metalloproteinase-9 as well as the chemokine CXCL-5. Furthermore, the profibrotic connective tissue growth factor was normalized, leading to a reduction in cardiac fibrosis despite severe hyperglycemia in mice lacking the B1 receptor. CONCLUSIONS These findings suggest that the B1 receptor is detrimental in diabetic cardiomyopathy in that it mediates inflammatory and fibrotic processes. These insights might have useful implications on future studies utilizing B1 receptor antagonists for treatment of human diabetic cardiomyopathy.
    Materialart: Online-Ressource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db08-0329
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2009
    ZDB Id: 1501252-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    Cardioprotective and Anti-Inflammatory Effects of Interleukin Converting Enzyme Inhibition in Experimental Diabetic Cardiomyopathy
    American Diabetes Association ; 2007
    In:  Diabetes Vol. 56, No. 7 ( 2007-07-01), p. 1834-1841
    Details
    In: Diabetes, American Diabetes Association, Vol. 56, No. 7 ( 2007-07-01), p. 1834-1841
    Kurzfassung: OBJECTIVE—We investigated the effect of pharmacological inhibition of the interleukin converting enzyme (ICE) on cardiac inflammation, apoptosis, fibrosis, and left ventricular function in an animal model of diabetes. RESEARCH DESIGN AND METHODS—Diabetes was induced in 24 Sprague-Dawley rats by injection of streptozotozin (STZ) (70 mg/kg). Diabetic animals were treated with the interleukin converting enzyme (ICE) inhibitor (ICEI) (n = 12) or with a placebo (n = 12). Nondiabetic rats served as controls (n = 12). Left ventricular function was documented 6 weeks after induction of diabetes. Cardiac tissue was analyzed for the expression of cytokines, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, leukocyte and macrophage integrins, and collagen. Phosphorylation of Akt was analyzed by Western blot and apoptosis by Blc-2 and Bax measurements. RESULTS—Left ventricular function was significantly impaired in diabetic animals. This was accompanied by a significant increase of cytokines, cell adhesion molecules, leukocytes and macrophages, and collagen content. In addition, the phosphorylation state of Akt was reduced. These changes were significantly attenuated in the diabetic group treated with ICEI. CONCLUSIONS—Cardiac dysfunction is associated with cardiac inflammation in experimental diabetic cardiomyopathy. Both of these—cardiac dysfunction and inflammation—are attenuated after treatment with ICEI. These data suggest that anticytokine-based therapies might be beneficial in diabetic cardiomyopathy.
    Materialart: Online-Ressource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db06-1662
    Sprache: Englisch
    Verlag: American Diabetes Association
    Publikationsdatum: 2007
    ZDB Id: 1501252-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
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    Online-Ressource
    TRIF Is a Critical Survival Factor in Viral Cardiomyopathy
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 186, No. 4 ( 2011-02-15), p. 2561-2570
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 4 ( 2011-02-15), p. 2561-2570
    Kurzfassung: TRIF is a member of the innate immune system known to be involved in viral recognition and type I IFN activation. Because IFNs are thought to play an important role in viral myocarditis, we investigated the role of TRIF in induced myocarditis in mice. Whereas C57BL/6 (wild-type) mice showed only mild myocarditis, including normal survival postinfection with coxsackievirus group B serotype 3 (CVB3), infection of TRIF−/− mice led to the induction of cardiac remodeling, severe heart failure, and 100% mortality (p & lt; 0.0001). These mice showed markedly reduced virus control in cardiac tissues and cardiomyocytes. This was accompained with dynamic cardiac cytokine activation in the heart, including a suppression of the antiviral cytokine IFN-β in the early viremic phase. TRIF−/− myocytes displayed a TLR4-dependent suppression of IFN-β, and pharmacological treatment of CVB3-infected TRIF−/− mice with murine IFN-β led to improved virus control and reduced cardiac inflammation. Additionally, this treatment within the viremic phase of myocarditis showed a significant long-term outcome indexed by reduced mortality (20 versus 100%; p & lt; 0.001). TRIF is essential toward a cardioprotection against CVB3 infection.
    Materialart: Online-Ressource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1002029
    RVK:
    XA 54100
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: The American Association of Immunologists
    Publikationsdatum: 2011
    ZDB Id: 1475085-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
    Online-Ressource
    Online-Ressource
    Accelerated Mitochondrial Adenosine Diphosphate/Adenosine Triphosphate Transport Improves Hypertension-Induced Heart Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Circulation Vol. 115, No. 3 ( 2007-01-23), p. 333-344
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 115, No. 3 ( 2007-01-23), p. 333-344
    Kurzfassung: Background— Strong evidence suggests that mitochondrial malfunction, which leads to disturbed energy metabolism and stimulated apoptosis, is a linchpin in the induction and manifestation of cardiac failure. An adequate exchange of ATP and ADP over the inner mitochondrial membrane by the adenine nucleotide translocase (ANT) is thereby essential to guarantee the cellular energy supply. Methods and Results— To explore the effect of an ameliorated mitochondrial ATP/ADP transportation on cardiac dysfunction, we generated transgenic rats overexpressing ANT1 in the heart (ANT rats) and crossed them with renin-overexpressing rats (REN rats) suffering from hypertension-induced cardiac insufficiency. Cardiac-specific ANT1 overexpression resulted in a higher ATP/ADP transportation and elevated activities of respiratory chain complexes. Increased ANT activity in double-transgenic (ANT/REN) animals did not influence excessive hypertension seen in REN rats. Hypertension-induced cardiac hypertrophy in the REN rats was prevented by parallel ANT1 overexpression, however, and left ventricular function remarkably improved. The ANT1 overexpression led to a reduction in fibrosis and an improvement in cardiac tissue architecture. Consequently, the survival rate of ANT/REN rats was enhanced. Further investigations into the cardioprotective mechanism of ANT1 overexpression revealed improved mitochondrial structure and function and significantly reduced apoptosis in ANT/REN rats, shown by lowered cytosolic/mitochondrial cytochrome c ratio, reduced caspase 3 level, and prevented DNA degradation. Conclusions— Myocardial ANT1 overexpression protects against hypertension-induced cardiac pathology. Thus, the improvement in mitochondrial function may be a basic principle for new strategies in treating heart disease.
    Materialart: Online-Ressource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.106.643296
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2007
    ZDB Id: 1466401-X
    Standort Signatur Einschränkungen Verfügbarkeit
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