Daniela Fraccarollo

Hannover Medical School, Hanover, Lower Saxony, Germany

Are you Daniela Fraccarollo?

Claim your profile

Publications (82)533.59 Total impact

  • Daniela Fraccarollo · Paolo Galuppo · Jonas Neuser · Johann Bauersachs · Julian D Widder ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction. Seven days after coronary artery ligation, rats were randomly allocated to treatment with PETN (80 mg/kg BID) or placebo for 9 weeks. Long-term PETN therapy prevented the progressive left ventricular dilatation and improved left ventricular contractile function and relaxation in rats with congestive heart failure. Mitochondrial superoxide anion production was markedly increased in the failing left ventricular myocardium and nearly normalized by PETN treatment. Gene set enrichment analysis revealed that PETN beneficially modulated the dysregulation of mitochondrial genes involved in energy metabolism, paralleled by prevention of uncoupling protein-3, thioredoxin-2, and superoxide dismutase-2 downregulation. Moreover, PETN provided a remarkable protective effect against reactive fibrosis in chronically failing hearts. Mechanistically, induction of heme oxygenase-1 by PETN prevented mitochondrial superoxide generation, NOX4 upregulation, and ensuing formation of extracellular matrix proteins in fibroblasts from failing hearts. In summary, PETN targeting reactive oxygen species generation prevented the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance. Therefore, PETN might be a promising therapeutic option in the treatment of ischemic heart diseases involving oxidative stress and impairment in nitric oxide bioactivity.
    Hypertension 09/2015; 66(5). DOI:10.1161/HYPERTENSIONAHA.115.05931 · 6.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Fibroblast Activation Protein α (FAP) is a membrane-bound serine protease expressed by activated fibroblasts during wound healing in the skin. Expression of FAP after myocardial infarction (MI) and potential effects on cardiac wound healing are largely unknown. Methods: MI was induced in rats and FAP expression was analyzed at 3, 7 and 28days post-MI by microarray, Western blot and immunohistochemistry. In human hearts after MI, a FAP(+) fibroblast population was identified, and characterized by immunohistochemistry for Prolyl-4-Hydroxylase β, α-smooth muscle actin, Thy-1 and vimentin. Signalling pathways leading to FAP expression were studied in human cardiac fibroblasts by Western blot and ELISA using TGFβ1, TGF-beta type I-receptor (TGFbR1)-inhibitor SB431542 or the MAPK-Inhibitor U0126 as well as siRNA targeting SMAD2 and SMAD3. Finally, fibroblasts were assayed for FAP-dependent migration (modified Boyden-chamber), proliferation (BrdU-assay) and gelatinolytic activity by gelatin zymography. Results: In rats, FAP expression was increased after MI especially in the peri-infarct area peaking at 7days post-MI. Co-localization analysis identified the majority of FAP(+) cells as activated proto-myofibroblasts and myofibroblasts. Concordantly, FAP(+) fibroblasts were abundant in ischemic tissue of human hearts after MI, but not in healthy control hearts. In vitro, FAP was induced by TGFβ1 via the canonical SMAD2/SMAD3 pathway. Depletion of FAP in fibroblasts reduced migratory capacity, while proliferation was not affected. Gelatin zymography revealed gelatinase activity by fibroblast-derived FAP. Conclusion: In this study, we show for the first time the expression of FAP in activated fibroblasts after MI and its activation by TGFβ1. Effects of FAP on fibroblast migration and gelatinolytic activity indicate a potential role in cardiac wound healing and remodeling.
    Journal of Molecular and Cellular Cardiology 08/2015; 87. DOI:10.1016/j.yjmcc.2015.08.016 · 4.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: AimsThe selective mineralocorticoid receptor (MR) antagonist eplerenone given early in patients with acute myocardial infarction (MI) improves clinical outcome, whereas little is known about the effectiveness of early spironolactone therapy. We aimed to compare the ability of eplerenone and spironolactone to promote cardiac repair after experimental MI.Methods and resultsStarting immediately after coronary artery ligation, C57BL/6J mice were treated with placebo, eplerenone, or spironolactone. At 7 days, treatment with eplerenone or spironolactone reduced thinning and expansion of healing infarct and improved early left ventricular chamber enlargement. Remarkably, eplerenone therapy resulted in significantly greater improvement than spironolactone of left ventricular contractile function and relaxation, associated with a more considerable leftward and downward shift of the pressure volume curve. Seven-day survival rate was significantly increased only in eplerenone treated mice. Moreover, eplerenone was superior to spironolactone in ameliorating neovessel formation in the injured myocardium. Optimized flow cytometry analysis of the monocyte differentiation marker Ly6C revealed predominant accumulation of Ly6Chigh monocytes/macrophages at the site of ischemic injury during the early inflammatory phase in placebo-treated mice. In contrast, MR antagonism, especially by eplerenone, led to a skewing of the monocyte/macrophage population toward a higher frequency of healing promoting Ly6Clow cells.Conclusion The MR antagonist eplerenone versus spironolactone showed superior efficacy during the acute MI phase with more beneficial effects on survival, early cardiac dilation, and functional decline. Modulation of monocyte maturation and enhanced infarct neovessel formation appears to play a pivotal role.
    ESC Heart Failure 07/2015; DOI:10.1002/ehf2.12053
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Platelet activation associated with endothelial dysfunction and impaired endogenous platelet inhibition is part of the cardiovascular phenotype of congestive heart failure (CHF) and contributes to the increased risk for thromboembolic complications. Pentaerythritol tetranitrate (PETN) has been shown to release nitric oxide without development of nitrate tolerance. We investigated the effect of chronic PETN treatment on platelet activation and aggregation in an experimental CHF model. Methods and results: Chronic ischemic heart failure was induced in male Wistar rats by coronary artery ligation. Starting 7 days thereafter, rats were randomised to placebo or PETN (80 mg/kg twice daily). After 9 weeks, activation of circulating platelets was determined measuring platelet bound fibrinogen, which requires activated glycoprotein IIb/IIIa on the platelet surface. Binding was quantified by flow-cytometry using a FITC-labelled anti-fibrinogen antibody. Platelet-bound fibrinogen was significantly increased in CHF-Placebo (mean fluorescence intensity: Sham 88±4, CHF-Placebo 104±6, p<0.05) and reduced following treatment with PETN (89±7, p<0.05 vs. CHF-Placebo). Maximal and final ADP-induced aggregation was significantly enhanced in CHF-Placebo vs. Sham-operated animals and normalized / decreased following chronic PETN treatment. Moreover, platelet adhesion was significantly reduced (number of adherent platelets: control: 85.6±5.5, PETN: 40±3.3; p<0.001) and VASP phosphorylation significantly enhanced following in vitro PETN treatment. Conclusion: Chronic NO supplementation using PETN reduces platelet activation in CHF rats. Thus, PETN may constitute a useful approach to prevent thromboembolic complications in CHF.
    PLoS ONE 04/2015; 10(4):e0123621. DOI:10.1371/journal.pone.0123621 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial nitric-oxide synthase (eNOS) uncoupling and increased inducible NOS (iNOS) activity amplify vascular oxidative stress. The role of inflammatory myelomonocytic cells as mediators of these processes and their impact on tetrahydrobiopterin availability and function have not yet been defined. Angiotensin II (ATII, 1 mg/kg/day for 7 days) increased Ly6Chigh and CD11b+/iNOShigh leukocytes and up-regulated levels of eNOS glutathionylation in aortas of C57BL/6 mice. Vascular iNOS-dependent NO formation was increased, whereas eNOS-dependent NO formation was decreased in aortas of ATII-infused mice as assessed by electron paramagnetic resonance (EPR) spectroscopy. Diphtheria toxin-mediated ablation of lysozyme M-positive (LysM+) monocytes in ATII-infused LysMiDTR transgenic mice prevented eNOS glutathionylation and eNOS-derived Nω-nitro-l-arginine methyl ester-sensitive superoxide formation in the endothelial layer. ATII increased vascular guanosine triphosphate cyclohydrolase I expression and biopterin synthesis in parallel, which was reduced in monocyte-depleted LysMiDTR mice. Vascular tetrahydrobiopterin was increased by ATII infusion but was even higher in monocyte-depleted ATII-infused mice, which was paralleled by a strong up-regulation of dihydrofolate reductase expression. EPR spectroscopy revealed that both vascular iNOS- and eNOS-dependent NO formation were normalized in ATII-infused mice following monocyte depletion. Additionally, deletion as well as pharmacologic inhibition of iNOS prevented ATII-induced endothelial dysfunction. In summary, ATII induces an inflammatory cell-dependent increase of iNOS, guanosine triphosphate cyclohydrolase I, tetrahydrobiopterin, NO formation, and nitro-oxidative stress as well as eNOS uncoupling in the vessel wall, which can be prevented by ablation of LysM+ monocytes.
    Journal of Biological Chemistry 08/2014; 289(40). DOI:10.1074/jbc.M114.604231 · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Peptides containing the asparagine-glycine-arginine (NGR) motif bind to aminopeptidase N (CD13), which is expressed on inflammatory cells, endothelial cells, and fibroblasts. It is unclear whether radiolabeled NGR-containing tracers could be used for in vivo imaging of the early wound-healing phase after myocardial infarction (MI) using positron emission tomography (PET). Procedures: Uptake of novel tracer [(68)Ga]NGR was assessed together with [(68)Ga]arginine-glycine-aspartic acid ([(68)Ga]RGD) and 2-deoxy-2-[(18) F]fluoro-D-glucose after myocardial ischemia/reperfusion (MI/R) injury using μ-PET and autoradiography, and relative expressions of CD13 and integrin β3 were assessed in fibroblasts, inflammatory cells, and endothelial cells by immunohistochemistry. Results: In the infarcted myocardium, uptake of [(68)Ga]NGR was maximal from days 3 to 7 after MI/R, and correlated with fibroblast and inflammatory cell infiltration as well as [(68)Ga]RGD uptake. Conclusions: [(68)Ga]NGR allows noninvasive and sequential determination of CD13 expression in fibroblasts and inflammatory cells by PET. This will facilitate monitoring of CD13 in the individual wound healing processes, allowing patient-specific therapies to improve outcome after MI.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 07/2014; 17(1). DOI:10.1007/s11307-014-0751-2 · 2.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling is involved in the pathogenesis of ischemic heart diseases, yet the impact of long-term sGC activation on progressive cardiac remodeling and heart failure after myocardial infarction (MI) has not been explored. Moreover, it is unknown whether stimulating the NO/heme-independent sGC provides additional benefits to ACE inhibition in chronic ischemic heart failure. Starting 10 days after MI, rats were treated with placebo, the sGC activator ataciguat (10 mg/kg/twice daily), ramipril (1 mg/kg/day), or a combination of both for 9 weeks. Long-term ataciguat therapy reduced left ventricular (LV) diastolic filling pressure and pulmonary edema, improved the rightward shift of the pressure-volume curve, LV contractile function and diastolic stiffness, without lowering blood pressure. NO/heme-independent sGC activation provided protection over ACE inhibition against mitochondrial superoxide production and progressive fibrotic remodeling, ultimately leading to a further improvement of cardiac performance, hypertrophic growth and heart failure. We found that ataciguat stimulating sGC activity was potentiated in (myo)fibroblasts during hypoxia-induced oxidative stress and that NO/heme-independent sGC activation modulated fibroblast-cardiomyocyte crosstalk in the context of heart failure and hypoxia. In addition, ataciguat inhibited human cardiac fibroblast differentiation and extracellular matrix protein production in response to TGF-β1. Overall, long-term sGC activation targeting extracellular matrix homeostasis conferred cardioprotection against progressive cardiac dysfunction, pathological remodeling and heart failure after myocardial infarction. NO/heme-independent sGC activation may prove to be a useful therapeutic target in patients with chronic heart failure and ongoing fibrotic remodeling.
    Archiv für Kreislaufforschung 07/2014; 109(4):421. DOI:10.1007/s00395-014-0421-1 · 5.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Unlabelled: Endothelial dysfunction and enhanced platelet reactivity in congestive heart failure (CHF) contribute to poor prognosis. CHF patients display an impaired responsiveness to clopidogrel. Fractalkine activates platelets and elevated plasma levels of this chemokine are a feature of CHF. We here addressed the interrelation of fractalkine, platelet reactivity and clopidogrel efficacy in humans and rats with CHF. Fractalkine serum levels determined by ELISA were increased in CHF patients (CHF: 1548 ± 650 pg/ml; Control: 968 ± 575 pg/ml, p<0.01) and following CHF induction in rats (CHF: 1509 ± 753 pg/ml; Sham: 1181 ± 275 pg/ml, p<0.05). Expression of fractalkine and its receptor CX3CR1 was enhanced in aortas of CHF rats as determined by immunofluorescence microscopy and molecular analysis. Fractalkine significantly aggravated endothelial dysfunction and augmented P-selectin expression on platelets from CHF rats. Platelet surface expression of CX3CR1 was increased in CHF rats, who displayed an impaired response to clopidogrel (platelet reactivity to ADP: CHF 30 ± 22%; Sham: 8 ± 5%, p<0.05). Similarly in humans with CHF, elevated fractalkine levels were accompanied by reduced clopidogrel responsiveness. Patients with high on-clopidogrel treatment platelet P2Y12 reactivity displayed higher fractalkine levels (1525 ± 487 pg/ml) than those with sufficient clopidogrel response (684 ± 315 pg/ml, p<0.01). In conclusion, in CHF fractalkine was increased on the endothelium and in blood serum, and platelet surface-expression of CX3CR1 was enhanced. Fractalkine diminished endothelial function beyond the impairment already observed in CHF and was associated with a reduced responsiveness to the platelet inhibitor clopidogrel. These findings may indicate a novel pathophysiological mechanism contributing to impaired clopidogrel responsiveness in CHF.
    Thrombosis and Haemostasis 12/2013; 111(4). DOI:10.1160/TH13-08-0640 · 4.98 Impact Factor
  • Ulrike Flierl · Daniela Fraccarollo · Jan Micka · Johann Bauersachs · Andreas Schäfer ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Platelet activation in congestive heart failure (CHF) contributes to an increased risk for thromboembolic complications. Rivaroxaban, the first oral direct FXa inhibitor is approved in Europe for prevention and treatment of venous thrombosis, pulmonary embolism, and prevention of thromboembolic events in atrial fibrillation. As heart failure is an important risk factor for thromboembolism and increased platelet activation is common in heart failure, we investigated the potential effect of Rivaroxaban treatment on platelets in an experimental CHF model. Methods and results: Chronic myocardial infarction was induced in male Wistar rats by coronary ligation. Rats were randomized to placebo or Rivaroxaban (3 and 10mg/kg once daily). After 10 weeks platelet activation was assessed. Platelet-bound fibrinogen, detected by flow-cytometry, was significantly increased in CHF-Placebo (p<0.05) and reduced following treatment with Rivaroxaban (p<0.05 vs. CHF-Placebo). ADP-induced aggregation was significantly enhanced in CHF-Placebo vs. sham-operated animals (p<0.05) and normalized following chronic FXa inhibition (p<0.05 vs. CHF-Placebo). In separate in vitro experiments, attenuated platelet aggregation was present after incubating whole blood directly with Rivaroxaban but absent when the experiment was performed in platelet-rich plasma only. Thus, a direct effect on platelets could be excluded. Conclusion: Chronic direct factor Xa inhibition using Rivaroxaban reduces platelet activation in CHF rats by attenuating the secondary phase of ADP-induced platelet aggregation. Thus, Rivaroxaban may constitute a useful approach to prevent thromboembolic complications and reduce platelet activation in CHF at the same time.
    Pharmacological Research 05/2013; 74. DOI:10.1016/j.phrs.2013.05.002 · 4.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Myocardial infarction (MI) leads to rapid necrosis of cardiac myocytes. To achieve tissue integrity and function, inflammatory cells are activated, including monocytes/macrophages. However, the effect of monocyte/macrophage recruitment after MI remains poorly defined. After experimental MI, monocytes and macrophages were depleted through serial injections of clodronate-containing liposomes. Monocyte/macrophage infiltration was reduced in the myocardium after MI by active treatment. Mortality was increased due to thromboembolic events in monocyte- and macrophage-depleted animals (92 vs. 33%; P<0.01). Left ventricular thrombi were detectable as early as 24 h after MI; this was reproduced in a genetic model of monocyte/macrophage ablation. A general prothrombotic state, increased infarct expansion, and deficient neovascularization were not observed. Severely compromised extracellular matrix remodeling (collagen I, placebo liposome vs. clodronate liposome, 2.4±0.2 vs. 0.8±0.2 arbitrary units; P<0.001) and locally lost integrity of the endocardium after MI are potential mechanisms. Patients with a left ventricular thrombus had a relative decrease of CD14(+)CD16(+) monocyte/macrophage subsets in the peripheral blood after MI (no thrombus vs. thrombus, 14.2±0.9 vs. 7.80±0.4%; P<0.05). In summary, monocytes/macrophages are of central importance for healing after MI. Impaired monocyte/macrophage function appears to be an unrecognized new pathophysiological mechanism for left ventricular thrombus development after MI.-Frantz, S., Hofmann, U., Fraccarollo, D., Schäfer, A., Kranepuhl, S., Hagedorn, I., Nieswandt, B., Nahrendorf, M., Wagner, H., Bayer, B., Pachel, C., Schön, M.P., Kneitz, S., Bobinger, T., Weidemann, F., Ertl, G., Bauersachs, J. Monocytes/macrophages prevent healing defects and left ventricular thrombus formation after myocardial infarction.
    The FASEB Journal 11/2012; 27(3). DOI:10.1096/fj.12-214049 · 5.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fractalkine (FKN) activates a G(αi) protein-coupled signaling pathway similar to the one activated by ADP via P2Y(12), which is the drug target of clopidogrel. FKN levels are increased under several disease conditions associated with impaired clopidogrel responsiveness. Blood samples were obtained from healthy volunteers and from 40 patients under chronic clopidogrel treatment. FKN reduced prostaglandin E1-induced vasodilator-stimulated phosphoprotein phosphorylation by ≈ 25% (P<0.01) at least partially mimicking the effect of ADP via P2Y(12). In vitro, FKN increased platelet reactivity index in clopidogrel-treated patients indicating potential activation of downstream targets of P2Y(12). When stratifying patients by their FKN levels, patients within the highest quartile of FKN (2042 ± 25 pg/mL) had the weakest response to clopidogrel (platelet reactivity index, 68 ± 4%), and patients within the lowest quartile (479 ± 50 pg/mL) had the strongest response (platelet reactivity index, 48 ± 7%; P=0.0106). FKN by itself induced phosphoinositide 3-kinase activation leading to Akt phosphorylation at Ser(473) (P<0.01 versus basal). In addition to desensitizing platelets to prostaglandin E1 via G(αi), FKN induces phosphoinositide 3-kinase-dependent Akt phosphorylation via a G(βγ) protein similar to ADP signaling through P2Y(12). FKN increased the platelet ADP response in clopidogrel-treated patients. Once released from an atherosclerotic lesion, this mechanism could contribute locally to impaired clopidogrel responsiveness at the vulnerable plaque.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2012; 32(8):1832-40. DOI:10.1161/ATVBAHA.112.250720 · 6.00 Impact Factor
  • Daniela Fraccarollo · Paolo Galuppo · Johann Bauersachs ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Adverse cardiac remodelling is a major cause of morbidity and mortality following acute myocardial infarction (MI). Mechanical and neurohumoral factors involved in structural and molecular post-infarction remodelling were important targets in research and treatment for years. More recently, therapeutic strategies that address myocardial regeneration and pathophysiological mechanisms of infarct wound healing appear to be useful novel tools to prevent progressive ventricular dilation, functional deterioration, life-threatening arrhythmia, and heart failure. This review provides an overview of future and emerging therapies for cardiac wound healing and remodelling after MI.
    Cardiovascular Research 03/2012; 94(2):293-303. DOI:10.1093/cvr/cvs109 · 5.94 Impact Factor
  • J. Bauersachs · D. Fraccarollo ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Myocardial infarction (MI) is one of the leading causes of death. Therapeutic strategies that target pathophysiological mechanisms of infarct healing and that improve cardiac remodeling after MI appear to be useful tools to prevent progressive myocardial dysfunction, heart failure and sudden death. Recent preclinical data highlight that activation of the mineralocorticoid receptor (MR) plays a pivotal role in post-infarct healing and remodelling. Immediate MR blockade after MI enhanced infarct neovascularization and reduced early myocardial dilatation and dysfunction. Moreover, cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure. This review summarizes new insights into the involvement of MR activation in wound healing and remodelling after myocardial infarction.
    European Heart Journal Supplements 06/2011; 13(Suppl B):B10-B14. DOI:10.1093/eurheartj/sur001 · 15.80 Impact Factor
  • Daniela Fraccarollo · Johann Bauersachs ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical trials have clearly demonstrated that mineralocorticoid receptor (MR) blockade improves outcome in patients with chronic systolic heart failure and left ventricular dysfunction after myocardial infarction; however, the underlying mechanisms as well as the cell-specific functional role of MR activation are still under investigation. Extrarenal effects of MR blockade on cardiovascular extracellular matrix turnover and oxidative stress, on myocardial structural and electrical remodeling, and on sympathoadrenergic stimulation, platelet activation, endothelial dysfunction, and macrophage polarization appear to be important mechanisms. Recent scientific advances, involving mice with cardiomyocyte-restricted inactivation of the MR gene suggest that the clinical benefits of MR blocking therapy in myocardial infarction and heart failure are mediated largely via cardiomyocyte-dependent mechanisms, and they provide strong evidence that more favorable effects on cardiac dysfunction and failure can be achieved by early initiation of MR blockade postinfarction.
    Trends in cardiovascular medicine 02/2011; 21(2):42-7. DOI:10.1016/j.tcm.2012.02.003 · 2.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR(MLCCre) mice. Chronically infarcted MR(MLCCre) mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O(2)(·-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR(MLCCre) mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-κB and reduced apoptosis early after myocardial infarction. Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression.
    Circulation 02/2011; 123(4):400-8. DOI:10.1161/CIRCULATIONAHA.110.983023 · 14.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Clopidogrel treatment in patients with coronary artery disease not only inhibits platelet activation but also improves endothelial function and nitric oxide (NO) bioavailability. Congestive heart failure (CHF) is associated with endothelial dysfunction and increased platelet activation. In rats with CHF following myocardial infarction (MI), we investigated whether treatment with clopidogrel modifies endothelial function. Eight weeks after coronary artery ligation, rats with CHF were randomized to placebo or the P2Y(12) receptor antagonist clopidogrel (5 mg/kg twice daily, given by gavage) for another 2 weeks. Afterwards, endothelial function was assessed in isolated aortic rings in organ bath experiments. Acetylcholine-induced, endothelium-dependent, nitric oxide-mediated vasorelaxation was significantly attenuated in CHF rats compared to sham-operated animals, and was significantly improved by treatment with clopidogrel. Adenosine-induced vasorelaxation via adenylyl cyclase stimulation was attenuated in CHF and significantly improved by clopidogrel. Increased vasoconstriction to phenylephrine was observed in CHF, particularly evident under cyclooxygenase inhibition, but prevented by clopidogrel treatment. Vasoconstriction by the P2Y(12) activator 2MeS-ADP was increased in CHF. Clopidogrel-treated CHF animals displayed enhanced phosphorylation of AKT and eNOS. In conclusion, clopidogrel improved endothelial function and NO bioavailability in heart failure. During CHF, sensitivity to P2Y(12) signaling was increased leading to impaired adenylyl cyclase-mediated signaling. Chronic P2Y(12)-blockade with clopidogrel improved adenylyl cyclase-mediated signaling including increased AKT- and eNOS-phosphorylation contributing to improved NO-mediated vasorelaxation.
    Archiv für Kreislaufforschung 02/2011; 106(3):485-94. DOI:10.1007/s00395-011-0153-4 · 5.41 Impact Factor
  • Andreas Schäfer · Daniela Fraccarollo · Lennart Werner · Johann Bauersachs ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial dysfunction and platelet activation due to impaired endogenous platelet inhibition by nitric oxide (NO) are part of the cardiovascular phenotype in congestive heart failure (CHF). We investigated whether chronic activation of the NO target enzyme soluble guanylyl cyclase (sGC) would beneficially modulate vascular function and platelet activation in experimental CHF. Chronic myocardial infarction was induced by coronary ligation in male Wistar rats. Animals were either treated with placebo or the sGC activator ataciguat (10 mg/kg/twice daily by gavage). After 10 weeks, hemodynamic assessment was performed and only animals with impaired left-ventricular end-diastolic pressures of more than 15 mmHg were included in the analysis. Vasomotor function was determined in organ bath studies. NO bioavailability was assessed by in vivo platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. P-selectin was determined as a marker of platelet degranulation. Endothelium-dependent, NO-mediated vasorelaxation as well as vascular sensitivity to exogenous NO were significantly impaired in aortic rings from CHF rats and normalised by ataciguat. In parallel, in vivo VASP phosphorylation reflecting NO bioavailability was significantly attenuated in platelets from CHF rats and normalised by ataciguat. Platelet activation, which was increased in CHF, was reduced by treatment with ataciguat. Chronic sGC activation improved vasomotor function and reduced platelet activation in CHF rats.
    Pharmacological Research 11/2010; 62(5):432-8. DOI:10.1016/j.phrs.2010.06.008 · 4.41 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We previously demonstrated that conditional overexpression of neuronal nitric oxide synthase (nNOS) inhibited L-type Ca2+ channels and decreased myocardial contractility. However, nNOS has multiple targets within the cardiac myocyte. We now hypothesize that nNOS overexpression is cardioprotective after ischemia/reperfusion because of inhibition of mitochondrial function and a reduction in reactive oxygen species generation. Ischemia/reperfusion injury in wild-type mice resulted in nNOS accumulation in the mitochondria. Similarly, transgenic nNOS overexpression caused nNOS abundance in mitochondria. nNOS translocation into the mitochondria was dependent on heat shock protein 90. Ischemia/reperfusion experiments in isolated hearts showed a cardioprotective effect of nNOS overexpression. Infarct size in vivo was also significantly reduced. nNOS overexpression also caused a significant increase in mitochondrial nitrite levels accompanied by a decrease of cytochrome c oxidase activity. Accordingly, O(2) consumption in isolated heart muscle strips was decreased in nNOS-overexpressing nNOS(+)/αMHC-tTA(+) mice already under resting conditions. Additionally, we found that the reactive oxygen species concentration was significantly decreased in hearts of nNOS-overexpressing nNOS(+)/αMHC-tTA(+) mice compared with noninduced nNOS(+)/αMHC-tTA(+) animals. We demonstrated that conditional transgenic overexpression of nNOS resulted in myocardial protection after ischemia/reperfusion injury. Besides a reduction in reactive oxygen species generation, this might be caused by nitrite-mediated inhibition of mitochondrial function, which reduced myocardial oxygen consumption already under baseline conditions.
    Circulation 10/2010; 122(16):1588-603. DOI:10.1161/CIRCULATIONAHA.109.933630 · 14.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the mechanisms underlying vascular endothelial and contractile dysfunction in diabetes as well as the effect of HMR1766, a novel nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC). Two weeks after induction of diabetes by streptozotocin, Wistar rats received either placebo or HMR1766 (10 mg/kg twice daily) for another 2 weeks; thereafter, vascular function was assessed. Endothelial function and contractile responses were significantly impaired, while vascular superoxide formation was increased in the aortae from diabetic versus healthy control rats. Using RNA microarrays, cytochrome P4502E1 (CYP2E1) was identified as the highest upregulated gene in diabetic aorta. CYP2E1 protein was significantly increased (16-fold) by diabetes, leading to a reduction in levels of the potent vasoconstrictor 20-hydroxy-eicosatetraenoic acid (20-HETE). Induction of CYP2E1 expression in healthy rats using isoniazide mimicked the diabetic noncontractile vascular response while preincubation of aortae from STZ-diabetic rats in vitro with 20-HETE rescued contractile function. Chronic treatment with the sGC activator HMR1766 improved NO sensitivity and endothelial function, reduced CYP2E1 expression and superoxide formation, enhanced 20-HETE levels, and reversed the contractile deficit observed in the diabetic rats that received placebo. Upregulation of CYP2E1 is essentially involved in diabetic vascular dysfunction. Chronic treatment with the sGC activator HMR1766 reduced oxidative stress, decreased CYP2E1 levels, and normalized vasomotor function in diabetic rats.
    Diabetes 08/2010; 59(8):2001-9. DOI:10.2337/db09-1668 · 8.10 Impact Factor
  • Source
    A Schafer · C Vogt · D Fraccarollo · J Widder · U Flierl · S K Hildemann · G Ertl · J Bauersachs ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes is associated with endothelial dysfunction and platelet activation, both of which contribute to increased cardiovascular risk. We investigated whether the selective mineralocorticoid receptor (MR) antagonist eplerenone improves endothelial dysfunction and reduces platelet activation in diabetic rats. Male Wistar-rats were injected with streptozotocin (50 mg/kg i.v.) to induce insulin-deficient diabetes. After 2 weeks, treatment with eplerenone (100 mg/kg/day) or vehicle was initiated for 2 weeks. Aortic superoxide production determined by lucigenin-enhanced chemiluminescence and 2-hydroxyethidium formation was significantly increased in rats with diabetes and reduced by treatment with eplerenone (chemiluminescence: control 2045+/-227, STZ-placebo 3977+/-340, p<0.05 vs. control, STZ-eplerenone 1762+/-307, p<0.05 vs. STZ-placebo). Endothelium-dependent vasorelaxation was significantly attenuated in diabetic rats and was normalized by eplerenone (maximum relaxation in % of precontraction: control 95+/-3, STZ-placebo 82+/-3, p<0.01 vs. control, STZ-eplerenone 99+/-1, p<0.01 vs. STZ-placebo). Treatment with the selective MR antagonist significantly reduced fibrinogen-binding on activated GPIIb/IIIa (immunofluorescence: control 161+/-7, STZ-placebo 208+/-16, p<0.05 vs. control, STZ-eplerenone 173+/-6, p<0.05 vs. STZ-placebo). Eplerenone improves endothelial function by reducing superoxide formation and increasing NO bioavailability in diabetic rats. Platelet activation was significantly reduced by eplerenone. Selective MR blockade may constitute a useful therapeutic approach for treatment of vascular dysfunction in diabetes.
    Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 02/2010; 61(1):45-52. · 2.39 Impact Factor

Publication Stats

3k Citations
533.59 Total Impact Points


  • 2011-2015
    • Hannover Medical School
      • Department of Cardiology and Angiology
      Hanover, Lower Saxony, Germany
  • 2000-2010
    • University of Wuerzburg
      • • Department of Internal Medicine I
      • • Department of Internal Medicine II
      Würzburg, Bavaria, Germany
  • 2005-2006
    • Technische Universität München
      München, Bavaria, Germany
  • 1997-2000
    • Universität Heidelberg
      • II. Medical Clinic
      Heidelburg, Baden-Württemberg, Germany