Publications (9)65.2 Total impact
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Article: Oxidative stress during mitochondrial biogenesis compromises mtDNA integrity in growing hearts and induces a global DNA repair response.
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ABSTRACT: Cardiomyocyte development in mammals is characterized by a transition from hyperplastic to hypertrophic growth soon after birth. The rise of cardiomyocyte cell mass in postnatal life goes along with a proportionally bigger increase in the mitochondrial mass in response to growing energy requirements. Relatively little is known about the molecular processes regulating mitochondrial biogenesis and mitochondrial DNA (mtDNA) maintenance during developmental cardiac hypertrophy. Genome-wide transcriptional profiling revealed the activation of transcriptional regulatory circuits controlling mitochondrial biogenesis in growing rat hearts. In particular, we detected a specific upregulation of factors involved in mtDNA expression and translation. More surprisingly, we found a specific upregulation of DNA repair proteins directly linked to increased oxidative damage during heart mitochondrial biogenesis, but only relatively minor changes in the mtDNA replication machinery. Our study paves the way for improved understanding of mitochondrial biogenesis, mtDNA maintenance and physiological adaptation processes in the heart and provides the first evidence for the recruitment of nucleotide excision repair proteins to mtDNA in cardiomyocytes upon DNA damage.Nucleic Acids Research 04/2012; 40(14):6595-607. · 8.03 Impact Factor -
Article: The Janus face of OSM-mediated cardiomyocyte dedifferentiation during cardiac repair and disease.
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ABSTRACT: Dedifferentiation is a common phenomenon among plants but has only been found rarely in vertebrates where it is mostly associated with regenerative responses such as formation of blastemae in amphibians to initiate replacement of lost body parts. Relatively little attention has been paid to dedifferentiation processes in mammals although a decline of differentiated functions and acquisition of immature, "embryonic" properties is seen in various disease processes. Dedifferentiation of parenchymal cells in mammals might serve multiple purposes including (1) facilitation of tissue regeneration by generation of progenitor-like cells and (2) protection of cells from hypoxia by reduction of ATP consumption due to changes in energy metabolism and/or inactivation of energy-intensive "specialized" functions. We recently found that an inflammatory cytokine of the interleukin 6 family, oncostatin M (OSM), initiates dedifferentiation of cardiomyocytes both in vitro and in vivo. Interestingly, activation of the OSM signaling pathway protects the heart from acute myocardial ischemia but has a negative impact when continuously activated thereby promoting dilative cardiomyopathy. The strong presence of the OSM receptor on cardiomyocytes and the unique features of the OSM signaling circuit suggest a major role of OSM for cardiac protection and repair. We propose that continuous activation or malfunctions of the cellular dedifferentiation machinery might contribute to different disease conditions.Cell cycle (Georgetown, Tex.) 02/2012; 11(3):439-45. · 5.36 Impact Factor -
Article: Oncostatin M is a major mediator of cardiomyocyte dedifferentiation and remodeling.
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ABSTRACT: Cardiomyocyte remodeling, which includes partial dedifferentiation of cardiomyocytes, is a process that occurs during both acute and chronic disease processes. Here, we demonstrate that oncostatin M (OSM) is a major mediator of cardiomyocyte dedifferentiation and remodeling during acute myocardial infarction (MI) and in chronic dilated cardiomyopathy (DCM). Patients suffering from DCM show a strong and lasting increase of OSM expression and signaling. OSM treatment induces dedifferentiation of cardiomyocytes and upregulation of stem cell markers and improves cardiac function after MI. Conversely, inhibition of OSM signaling suppresses cardiomyocyte remodeling after MI and in a mouse model of DCM, resulting in deterioration of heart function after MI but improvement of cardiac performance in DCM. We postulate that dedifferentiation of cardiomyocytes initially protects stressed hearts but fails to support cardiac structure and function upon continued activation. Manipulation of OSM signaling provides a means to control the differentiation state of cardiomyocytes and cellular plasticity.Cell stem cell 11/2011; 9(5):420-32. · 23.56 Impact Factor -
Article: Nitric oxide-associated protein 1 (NOA1) is necessary for oxygen-dependent regulation of mitochondrial respiratory complexes.
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ABSTRACT: In eukaryotic cells, maintenance of cellular ATP stores depends mainly on mitochondrial oxidative phosphorylation (OXPHOS), which in turn requires sufficient cellular oxygenation. The crucial role of proper oxygenation for cellular viability is reflected by involvement of several mechanisms, which sense hypoxia and regulate activities of respiratory complexes according to available oxygen concentrations. Here, we focus on mouse nitric oxide-associated protein 1 (mNOA1), which has been identified as an important component of the machinery that adjusts OXPHOS activity to oxygen concentrations. mNOA1 is an evolutionary conserved GTP-binding protein that is involved in the regulation of mitochondrial protein translation and respiration. We found that mNOA1 is located mostly in the mitochondrial matrix from where it interacts with several high molecular mass complexes, most notably with the complex IV of the respiratory chain and the prohibitin complex. Knock-down of mNOA1 impaired enzyme activity I+III, resulting in oxidative stress and eventually cell death. mNOA1 is transcriptionally regulated in an oxygen-sensitive manner. We propose that oxygen-dependent regulation of mNOA1 is instrumental to adjusting OXPHOS activity to oxygen availability, thereby controlling mitochondrial metabolism.Journal of Biological Chemistry 07/2011; 286(37):32086-93. · 4.77 Impact Factor -
Article: Induction of smooth muscle cell migration during arteriogenesis is mediated by Rap2.
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ABSTRACT: Collateral artery growth or arteriogenesis is the primary means of the circulatory system to maintain blood flow in the face of major arterial occlusions. Arteriogenesis depends on activation of fibroblast growth factor (FGF) receptors, but relatively little is known about downstream mediators of FGF signaling. We screened for signaling components that are activated in response to administration of FGF-2 to cultured vascular smooth muscle cells (VSMCs) and detected a significant increase of Rap2 but not of other Ras family members, which corresponded to a strong upregulation of Rap2 and C-Raf in growing collaterals from rabbits with femoral artery occlusion. Small interfering RNAs directed against Rap2 did not affect FGF-2 induced proliferation of VSMC but strongly inhibited their migration. Inhibition of FGF receptor-1 (FGFR1) signaling by infusion of a sulfonic acid polymer or infection with a dominant-negative FGFR1 adenovirus inhibited Rap2 upregulation and collateral vessel growth. Similarly, expression of dominant-negative Rap2 blocked arteriogenesis, whereas constitutive active Rap2 enhanced collateral vessel growth. Rap2 is part of the arteriogenic program and acts downstream of the FGFR1 to stimulate VSMC migration. Specific modulation of Rap2 might be an attractive target to manipulate VSMC migration, which plays a role in numerous pathological processes.Arteriosclerosis Thrombosis and Vascular Biology 07/2011; 31(10):2297-305. · 6.37 Impact Factor -
Article: Identification of right heart-enriched genes in a murine model of chronic outflow tract obstruction.
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ABSTRACT: The right ventricle (RV) differs in several aspects from the left ventricle (LV) including its embryonic origin, physiological role and anatomical design. In contrast to LV hypertrophy, little is known about the molecular circuits, which are activated upon RV hypertrophy (RVH). We established a highly reproducible model of RVH in mice using pulmonary artery clipping (PAC), which avoids detrimental RV pressure overload and thus allows long-term survival of operated mice. Magnetic resonance imaging revealed pathognomonic changes with striking similarities to human congenital heart disease- or pulmonary arterial hypertension-patients. Comparative, microarray based transcriptome analysis of right- and left-ventricular remodeling identified distinct transcriptional responses to pressure-induced hypertrophy of either ventricle, which were mainly characterized by stronger transcriptional responses of the RV compared to the LV myocardium. Hierarchic cluster analysis revealed a RV- and LV-specific pattern of gene activity after induction of hypertrophy, however, we did not find evidence for qualitatively distinct regulatory pathways in RV compared to LV. Data mining of nearly three thousand RV-enriched genes under PAC disclosed novel potential (co)-regulators of long-term RV remodeling and hypertrophy. We reason that specific inhibitory mechanisms in RV restrict excessive myocardial hypertrophy and thereby contribute to its vulnerability to pressure overload.Journal of Molecular and Cellular Cardiology 10/2010; 49(4):598-605. · 5.17 Impact Factor -
Article: TFAM-dependent and independent dynamics of mtDNA levels in C2C12 myoblasts caused by redox stress.
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ABSTRACT: TFAM is an essential protein factor for the initiation of transcription of the mtDNA. It also functions as a packaging factor, which stabilizes the mtDNA pool. To investigate the regulatory role of TFAM for regeneration and proliferation of the mtDNA pool, we exposed the muscle cell line C2C12 to a severe redox stress (H2O2) or to a moderate redox stress (GSH depletion), determined the dynamics of the mtDNA levels and correlated this with the TFAM protein levels. H2O2 caused a concentration-dependent loss of mtDNA molecules. The mtDNA levels recovered slowly within 3 days after H2O2 stress. The TFAM protein was less degraded than the mtDNA indicating an accumulation of TFAM protein per mtDNA after H2O2 stress. Overexpression of TFAM did not protect against the mtDNA loss after H2O2 stress but shortened the recovery time. GSH depletion led to a proliferation of the mtDNA pool. Although the mtDNA levels increased the TFAM protein levels were unaffected by the GSH depletion. We conclude that the accumulation of the TFAM protein after H2O2 stress contributes to the regeneration of the mtDNA pool but that other mechanisms, independent from the TFAM protein amount have to be postulated to explain the proliferation of the mtDNA pool after GSH depletion.Biochimica et Biophysica Acta 03/2006; 1760(2):141-50. · 4.66 Impact Factor -
Article: Serial competitive RT-PCR using multiple standards.
BioTechniques 11/2002; 33(4):744, 746, 748. · 2.67 Impact Factor -
Article: Increased expression of endothelin-converting enzyme-1 in failing human myocardium.
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ABSTRACT: Endothelin-1 (ET-1) is considered to be involved in the development and progression of heart failure. Therefore, we analysed the expression of endothelin-converting enzyme-1 (ECE-1), endothelin receptors A (ET(A)) and B (ET(B)) mRNAs by standard-calibrated, competitive reverse transcriptase-PCR using an internal-deleted in vitro-transcribed cRNA standard. ET-1 peptide levels were measured using isoform-specific rabbit antibodies against synthetic ET-1. mRNA and protein expression was determined in the right atrial myocardium of New York Heart Association class I patients and class IV patients undergoing aorto-coronary bypass surgery. ECE-1 mRNA was upregulated in failing atrial myocardium. Furthermore, ET-1 peptide levels were increased in failing atrial myocardium. Atrial ET(A) mRNA expression was not changed, while ET(B) mRNA was downregulated in the failing atrial myocardium. Our results support an upregulation of ET-1 synthesis by induction of ECE-1 in failing atrial myocardium. Pharmacological inhibition of augmented ECE-1 expression might provide a new therapeutic perspective in the treatment of heart failure.Clinical Science 09/2002; 103 Suppl 48:237S-240S. · 4.61 Impact Factor
Top co-authors
Top Journals
Institutions
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2011–2012
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Max-Planck-Institut für Herz- und Lungenforschung
Bad Nauheim, Hesse, Germany
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2010
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Justus-Liebig-Universität Gießen
Gießen, Hesse, Germany
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2006
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Martin-Luther-Universität Halle-Wittenberg
- Institut für Pathologie
Halle, Saxony-Anhalt, Germany
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