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

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, Junichi Sadoshima, Peter J Meikle, Natalie A Mellett, Elizabeth A Woodcock, Silvana Marasco, Tomomi Ueyama, Xiao-Jun Du, Mark A Febbraio, Julie R McMullen

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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.
Original languageEnglish
Article number5705
Pages (from-to)1 - 16
Number of pages16
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 2014

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