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The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice
journal contributionposted on 2016-11-03, 06:06 authored by Geeta Sapra, Yow Keat Tham, Nelly Cemerlang, Aya Matsumoto, Helen Kiriazis, Bianca Bernardo, Darren Henstridge, Jenny Ooi, Lynette PretoriusLynette Pretorius, Esther Boey, Lydia Lim, Junichi Sadoshima, Peter Meikle, Natalie Mellet, Elizabeth Woodcock, Silvana Marasco, Tomomi Ueyama, Xiao-Jun Du, Mark Febbraio, Julie McMullen
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.