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         headline:Gene expression analysis to identify mechanisms underlying heart failure susceptibility in mice and humans
         description:Genetic factors are known to modulate cardiac susceptibility to ventricular hypertrophy and failure. To determine how strain influences the transcriptional response to pressure overload-induced heart failure (HF) and which of these changes accurately reflect the human disease, we analyzed the myocardial transcriptional profile of mouse strains with high (C57BL/6J) and low (129S1/SvImJ) susceptibility for HF development, which we compared to that of human failing hearts. Following transverse aortic constriction (TAC), C57BL/6J mice developed overt HF while 129S1/SvImJ did not. Despite a milder aortic constriction, impairment of ejection fraction and ventricular remodeling (dilation, fibrosis) was more pronounced in C57BL/6J mice. Similarly, changes in myocardial gene expression were more robust in C57BL/6J (461 genes) compared to 129S1/SvImJ mice (71 genes). When comparing these patterns to human dilated cardiomyopathy (1344 genes), C57BL/6J mice tightly grouped to human hearts. Overlay and bioinformatic analysis of the transcriptional profiles of C57BL/6J mice and human failing hearts identified six co-regulated genes (POSTN, CTGF, FN1, LOX, NOX4, TGFB2) with established link to HF development. Pathway enrichment analysis identified angiotensin and IGF-1 signaling as most enriched putative upstream regulator and pathway, respectively, shared between TAC-induced HF in C57BL/6J mice and in human failing hearts. TAC-induced heart failure in C57BL/6J mice more closely reflects the gene expression pattern of human dilated cardiomyopathy compared to 129S1/SvImJ mice. Unbiased as well as targeted gene expression and pathway analyses identified periostin, angiotensin signaling, and IGF-1 signaling as potential causes of increased HF susceptibility in C57BL/6J mice and as potentially useful drug targets for HF treatment.
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      name:Natalie Hoppe
      affiliation:
            name:Freiburg University
            address:
               name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
               type:PostalAddress
            type:Organization
      name:Michael M. Hoffmann
      affiliation:
            name:University of Freiburg
            address:
               name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
               type:PostalAddress
            type:Organization
            name:University of Freiburg
            address:
               name:Institute for Clinical Chemistry and Laboratory Medicine, Medical Center, University of Freiburg, Freiburg, Germany
               type:PostalAddress
            type:Organization
      name:Katja E. Odening
      affiliation:
            name:Freiburg University
            address:
               name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
               type:PostalAddress
            type:Organization
            name:University of Freiburg
            address:
               name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
               type:PostalAddress
            type:Organization
      name:Samuel Sossalla
      affiliation:
            name:University Hospital Regensburg
            address:
               name:Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
               type:PostalAddress
            type:Organization
      name:Andreas Zirlik
      affiliation:
            name:Freiburg University
            address:
               name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
               type:PostalAddress
            type:Organization
            name:University of Freiburg
            address:
               name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
               type:PostalAddress
            type:Organization
      name:Lutz Hein
      affiliation:
            name:University of Freiburg
            address:
               name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
               type:PostalAddress
            type:Organization
            name:University of Freiburg
            address:
               name:Institute of Experimental and Clinical Pharmacology, BIOSS Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany
               type:PostalAddress
            type:Organization
      name:Christoph Bode
      affiliation:
            name:Freiburg University
            address:
               name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
               type:PostalAddress
            type:Organization
            name:University of Freiburg
            address:
               name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
               type:PostalAddress
            type:Organization
      name:Adam R. Wende
      affiliation:
            name:University of Alabama at Birmingham
            address:
               name:Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Heiko Bugger
      affiliation:
            name:Freiburg University
            address:
               name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
               type:PostalAddress
            type:Organization
            name:University of Freiburg
            address:
               name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
      name:Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, USA
      name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
      name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
      name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
      name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
      name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
      name:Institute for Clinical Chemistry and Laboratory Medicine, Medical Center, University of Freiburg, Freiburg, Germany
      name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
      name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
      name:Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
      name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
      name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
      name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
      name:Institute of Experimental and Clinical Pharmacology, BIOSS Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany
      name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
      name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
      name:Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, USA
      name:Cardiology and Angiology I, Heart Center, Freiburg University, Freiburg, Germany
      name:Faculty of Medicine, University of Freiburg, Freiburg, Germany
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