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Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth

Abstract

Ability of the heart to undergo pathological or physiological hypertrophy upon increased wall stress is critical for long-term compensatory function in response to increased workload demand. While substantial information has been published on the nature of the fundamental molecular signaling involved in hypertrophy, the role of extracellular matrix protein Fibronectin (Fn) in hypertrophic signaling is unclear. The objective of the study was to delineate the role of Fn during pressure overload-induced pathological cardiac hypertrophy and physiological growth prompted by exercise. Genetic conditional ablation of Fn in adulthood blunts cardiomyocyte hypertrophy upon pressure overload via attenuated activation of nuclear factor of activated T cells (NFAT). Loss of Fn delays development of heart failure and improves survival. In contrast, genetic deletion of Fn has no impact on physiological cardiac growth induced by voluntary wheel running. Down-regulation of the transcription factor c/EBPβ (Ccaat-enhanced binding protein β), which is essential for induction of the physiological growth program, is unaffected by Fn deletion. Nuclear NFAT translocation is triggered by Fn in conjunction with up-regulation of the fetal gene program and hypertrophy of cardiomyocytes in vitro. Furthermore, activation of the physiological gene program induced by insulin stimulation in vitro is attenuated by Fn, whereas insulin had no impact on Fn-induced pathological growth program. Fn contributes to pathological cardiomyocyte hypertrophy in vitro and in vivo via NFAT activation. Fn is dispensable for physiological growth in vivo, and Fn attenuates the activation of the physiological growth program in vitro.

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Acknowledgments

This study was supported by grants of the National Institute of Health to M. Sussman (R01HL067245, R01HL105759, R01HL113656, R21HL102613, R21HL104544, R21HL102714, R37HL091102, RC1HL100891), and to M. Quintana (SDSU MARC 5T34GM008303-23), by a pre-doctoral fellowship of the American Heart Association to S. Din (12PRE12060248) and the Deutsche Forschungsgemeinschaft DFG (1659/1-1 to M. Völkers and 3900/1-1 to M. Konstandin). We would like to thank Prof. Dr. Reinhard Fässler for generously providing Fnfl/fl mice.

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Correspondence to Mark A. Sussman.

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Konstandin, M.H., Völkers, M., Collins, B. et al. Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth. Basic Res Cardiol 108, 375 (2013). https://doi.org/10.1007/s00395-013-0375-8

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  • DOI: https://doi.org/10.1007/s00395-013-0375-8

Keywords

  • Cardiomyocytes
  • Pathological and physiological hypertrophy
  • Fibronectin
  • Heart failure