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Gene expression analysis to identify mechanisms underlying heart failure susceptibility in mice and humans

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Abstract

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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Acknowledgements

We thank Dr. Dietmar Pfeifer at the University of Freiburg for technical assistance in performing microarray analyses.

Funding

This study was supported by a research grant of the Deutsche Forschungsgemeinschaft to H.B. (Bu2126/3-1), and by a National Institutes of Health (NIH) grant to A.R.W. (HL133011). Training support was provided by NIH T32 to M.E.P. (T32HD071866).

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Author notes

  1. Christoph Koentges and Mark E. Pepin contributed equally. Adam R. Wende and Heiko Bugger contributed equally.

Authors and Affiliations

  1. Cardiology and Angiology I, Heart Center, Freiburg University, Hugstetter Str. 55, 79106, Freiburg, Germany

    Christoph Koentges, Carolyn Müsse, Katharina Pfeil, Sonia V. Viteri Alvarez, Natalie Hoppe, Katja E. Odening, Andreas Zirlik, Christoph Bode & Heiko Bugger

  2. Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, 901 19th Street South, BMR2 Rm 506, Birmingham, AL, 35294, USA

    Mark E. Pepin & Adam R. Wende

  3. Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Michael M. Hoffmann, Katja E. Odening, Andreas Zirlik, Lutz Hein, Christoph Bode & Heiko Bugger

  4. Institute for Clinical Chemistry and Laboratory Medicine, Medical Center, University of Freiburg, Freiburg, Germany

    Michael M. Hoffmann

  5. Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany

    Samuel Sossalla

  6. Institute of Experimental and Clinical Pharmacology, BIOSS Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany

    Lutz Hein

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  1. Christoph Koentges
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Correspondence to Adam R. Wende or Heiko Bugger.

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Koentges, C., Pepin, M.E., Müsse, C. et al. Gene expression analysis to identify mechanisms underlying heart failure susceptibility in mice and humans. Basic Res Cardiol 113, 8 (2018). https://doi.org/10.1007/s00395-017-0666-6

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  • DOI: https://doi.org/10.1007/s00395-017-0666-6

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