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. 2014 Dec 9:5:5705.
doi: 10.1038/ncomms6705.

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

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

Geeta Sapra et al. Nat Commun. .
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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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