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Mahmoodzadeh S.,Charite - Medical University of Berlin | Dworatzek E.,Charite - Medical University of Berlin | Fritschka S.,Charite - Medical University of Berlin | Pham T.H.,Charite - Medical University of Berlin | And 2 more authors.
Cardiovascular Research | Year: 2010

AimsFemale sex and sex hormones contribute to cardiac remodelling. 17β-estradiol (E2) is involved in the modulation of extracellular matrix composition and function. Here, we analysed the effect of E2 on matrix metalloproteinase (MMP)-2 gene expression and studied the underlying molecular mechanisms in rat cardiac fibroblasts and in a human fibroblast cell line.Methods and resultsIn adult rat cardiac fibroblasts, E2 significantly decreased MMP-2 gene expression in an estrogen receptor (ER)-dependent manner. Transient transfection experiments of human MMP-2 (hMMP-2) promoter deletion constructs in a human fibroblast cell line revealed a regulatory region between-324 and-260 bp that is involved in E2/ER-mediated repression of hMMP-2 gene transcription. Electrophoretic mobility shift assays (EMSA) and supershift analysis demonstrated the binding of transcription factor Elk-1 within this promoter region. Elk-1 was phosphorylated by E2 via the mitogen-activated protein kinase (MAPK) signalling pathway as shown by western blotting. Treatment of cells with the MAPK inhibitor PD98059 blocked the E2-dependent repression of hMMP-2 promoter activity as well as the endogenous MMP-2 mRNA levels in both human fibroblast cells and rat cardiac fibroblasts.ConclusionE2 inhibits MMP-2 expression via the ER and the MAPK pathway in rat cardiac fibroblasts and in a human fibroblast cell line. These mechanisms may contribute to sex-specific differences in fibrotic processes that are observed in human heart and other diseases. Source


Kuebler W.M.,Li Ka Shing Knowledge Institute | Kuebler W.M.,University of Toronto | Kuebler W.M.,Charite - Medical University of Berlin | Kuebler W.M.,German Heart Institute Berlin
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2011

FOLLOWING ITS IDENTIFICATION as the long-searched-for endothelial-derived relaxing factor and the subsequent recognition of its additional anti-inflammatory and antiaggregatory properties, nitric oxide (NO) was initially hailed as the new universal therapeutic weapon in pathologies associated with hypertension, inflammation, and/or coagulation. Hopes were particularly high for the treatment of acute lung injury (ALI), which characteristically displays all of these pathological features. Yet, although clinical trials showed initial improvement of oxygenation with inhalation of NO, these effects were not sustained and did not reduce mortality (8). These and other studies led to the realization that the role of NO in ALI and permeability-type lung edema is much more complex, in that NO, based on its site of action and interaction partners, may have both protective and detrimental effects. In the past, the beneficial effects of NO have at large been attributed to activation of its molecular target soluble guanylyl cyclase (sGC) and the formation of the second messenger 3′,5′-cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), whereas barrier-disruptive effects were ascribed to the formation of peroxynitrite (ONOO-) in the presence of superoxide (O2-) or conjecturally to S-nitrosylation of junctional proteins (15). Recent evidence, however, demonstrates that cGMP signaling by itself may play an ambivalent role in vascular barrier regulation, a recognition that not only incites new scientific perspectives and challenges but may be of considerable clinical relevance given the pending introduction of sGC activators as novel therapeutic strategy in cardiopulmonary disease (18). © 2011 the American Physiological Society. Source


Shakibaei M.,Ludwig Maximilians University of Munich | Mobasheri A.,University of Nottingham | Lueders C.,German Heart Institute Berlin | Busch F.,Ludwig Maximilians University of Munich | And 2 more authors.
PLoS ONE | Year: 2013

Objective: Development of treatment resistance and adverse toxicity associated with classical chemotherapeutic agents highlights the need for safer and effective therapeutic approaches. Herein, we examined the effectiveness of a combination treatment regimen of 5-fluorouracil (5-FU) and curcumin in colorectal cancer (CRC) cells. Methods: Wild type HCT116 cells and HCT116+ch3 cells (complemented with chromosome 3) were treated with curcumin and 5-FU in a time- and dose-dependent manner and evaluated by cell proliferation assays, DAPI staining, transmission electron microscopy, cell cycle analysis and immunoblotting for key signaling proteins. Results: The individual IC50 of curcumin and 5-FU were approximately 20 μM and 5 μM in HCT116 cells and 5 μM and 1 μM in HCT116+ch3 cells, respectively (p<0.05). Pretreatment with curcumin significantly reduced survival in both cells; HCT116+ch3 cells were considerably more sensitive to treatment with curcumin and/or 5-FU than wild-type HCT116 cells. The IC50 values for combination treatment were approximately 5 μM and 1 μM in HCT116 and 5 μM and 0.1 μM in HCT116+ch3, respectively (p<0.05). Curcumin induced apoptosis in both cells by inducing mitochondrial degeneration and cytochrome c release. Cell cycle analysis revealed that the anti-proliferative effect of curcumin and/or 5-FU was preceded by accumulation of CRC cells in the S cell cycle phase and induction of apoptosis. Curcumin potentiated 5-FU-induced expression or cleavage of pro-apoptotic proteins (caspase-8, -9, -3, PARP and Bax), and down-regulated anti-apoptotic (Bcl-xL) and proliferative (cyclin D1) proteins. Although 5-FU activated NF-κB/PI-3K/Src pathway in CRC cells, this was down-regulated by curcumin treatment through inhibition of IκBα kinase activation and IκBα phosphorylation. Conclusions: Combining curcumin with conventional chemotherapeutic agents such as 5-FU could provide more effective treatment strategies against chemoresistant colon cancer cells. The mechanisms involved may be mediated via NF-κB/PI-3K/Src pathways and NF-κB regulated gene products. © 2013 Shakibaei et al. Source


Manka R.,German Heart Institute Berlin
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance | Year: 2010

The purpose of this study was to determine the ability of blood oxygen level dependent (BOLD) cardiovascular magnetic resonance (CMR) to detect stress-inducible myocardial ischemic reactions in the presence of angiographically significant coronary artery disease (CAD). Forty-six patients (34 men; age 65 ± 9 years,) with suspected or known coronary artery disease underwent CMR at 3Tesla prior to clinically indicated invasive coronary angiography. BOLD CMR was performed in 3 short axis slices of the heart at rest and during adenosine stress (140 μg/kg/min) followed by late gadolinium enhancement (LGE) imaging. In all 16 standard myocardial segments, T2* values were derived at rest and under adenosine stress. Quantitative coronary angiography served as the standard of reference and defined normal myocardial segments (i.e. all 16 segments in patients without any CAD), ischemic segments (i.e. supplied by a coronary artery with ≥50% luminal narrowing) and non-ischemic segments (i.e. supplied by a non-significantly stenosed coronary artery in patients with significant CAD). Coronary angiography demonstrated significant CAD in 23 patients. BOLD CMR at rest revealed significantly lower T2* values for ischemic segments (26.7 ± 11.6 ms) compared to normal (31.9 ± 11.9 ms; p < 0.0001) and non-ischemic segments (31.2 ± 12.2 ms; p = 0.0003). Under adenosine stress T2* values increased significantly in normal segments only (37.2 ± 14.7 ms; p < 0.0001). Rest and stress BOLD CMR at 3Tesla proved feasible and differentiated between ischemic, non-ischemic, and normal myocardial segments in a clinical patient population. BOLD CMR during vasodilator stress identified patients with significant CAD. Source


Ricken T.,University of Duisburg - Essen | Dahmen U.,University of Duisburg - Essen | Dirsch O.,German Heart Institute Berlin
Biomechanics and Modeling in Mechanobiology | Year: 2010

Liver resection can lead to focal outflow obstruction due to transection of hepatic veins. Outflow obstruction may cause additional damage to the small remnant liver. Drainage of the obstructed territories is reestablished via dilatation of sinusoids. Subsequently, sinusoidal canals are formed draining the blood from the obstructed territory to the neighboring unobstructed territories. We raised the phenomenological hypothesis that the blood pressure gradient is the main driving force for the formation of sinusoidal vascular canals. We generated a biphasic mechanical model to describe this vascular remodeling process in relation to the variable pressure gradient. Therefore, we introduced a transverse isotropic permeability relation aswell as an evolutional optimization rule to describe the relationship between pressure gradient and the direction of the sinusoidal blood flow in the fluid phase. As a next step, we developed a framework for the calculation concept including the representation of the governing weak formulations. Then, we examined a representative numerical example with simulation of the blood flow under both conditions, the physiological situation as well as after outflow obstruction. Doing so, we were able to reproduce numerically the experimentally observed process of reestablishing hepatic venous drainage via redirection of blood flow and formation of new vascular structures in respect to the fluid flow. The calculated results support the hypothesis that the reorientation of blood flow mainly depends on the pressure gradient. Further investigations are needed to determine the micromechanical influences on the reorientation of the sinusoids. © Springer-Verlag 2010. Source

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