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The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

Author

Listed:
  • Geeta Sapra

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Yow Keat Tham

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Nelly Cemerlang

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Aya Matsumoto

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Helen Kiriazis

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Bianca C. Bernardo

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Darren C. Henstridge

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Jenny Y. Y. Ooi

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Lynette Pretorius

    (Baker IDI Heart and Diabetes Institute, PO Box 6492
    Monash University)

  • Esther J. H. Boey

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Lydia Lim

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Junichi Sadoshima

    (Rutgers New Jersey Medical School, The State University of New Jersey)

  • Peter J. Meikle

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Natalie A. Mellet

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Elizabeth A. Woodcock

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Silvana Marasco

    (Heart Centre, Alfred Hospital)

  • Tomomi Ueyama

    (Graduate School of Medical Science, Kyoto Prefectural University of Medicine)

  • Xiao-Jun Du

    (Baker IDI Heart and Diabetes Institute, PO Box 6492)

  • Mark A. Febbraio

    (Baker IDI Heart and Diabetes Institute, PO Box 6492
    Monash University)

  • Julie R. McMullen

    (Baker IDI Heart and Diabetes Institute, PO Box 6492
    Monash University)

Abstract

Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.

Suggested Citation

  • Geeta Sapra & Yow Keat Tham & Nelly Cemerlang & Aya Matsumoto & Helen Kiriazis & Bianca C. Bernardo & Darren C. Henstridge & Jenny Y. Y. Ooi & Lynette Pretorius & Esther J. H. Boey & Lydia Lim & Junic, 2014. "The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice," Nature Communications, Nature, vol. 5(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6705
    DOI: 10.1038/ncomms6705
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