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

  • Nat Commun. 2014 Dec 9;5:5705. doi: 10.1038/ncomms6705.
Geeta Sapra  1 ,  Yow Keat Tham  1 ,  Nelly Cemerlang  1 ,  Aya Matsumoto  1 ,  Helen Kiriazis  1 ,  Bianca C Bernardo  1 ,  Darren C Henstridge  1 ,  Jenny Y Y Ooi  1 ,  Lynette Pretorius  2 ,  Esther J H Boey  1 ,  Lydia Lim  1 ,  Junichi Sadoshima  3 ,  Peter J Meikle  1 ,  Natalie A Mellet  1 ,  Elizabeth A Woodcock  1 ,  Silvana Marasco  4 ,  Tomomi Ueyama  5 ,  Xiao-Jun Du  1 ,  Mark A Febbraio  2 ,  Julie R McMullen  2
Affiliations
  • 1. Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
  • 2. 1] Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia [2] Monash University, Melbourne, Victoria 3800, Australia.
  • 3. Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, New Jersey 07103, USA.
  • 4. Heart Centre, Alfred Hospital, Melbourne, Victoria 3004, Australia.
  • 5. Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
PMID: 25489988 DOI: 10.1038/ncomms6705
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.

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