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

• Published in: Nature communications 2014-12, Vol.5 (1), p.5705-5705, Article 5705
• Main Authors: Sapra, Geeta, Tham, Yow Keat, Cemerlang, Nelly, Matsumoto, Aya, Kiriazis, Helen, Bernardo, Bianca C., Henstridge, Darren C., Ooi, Jenny Y. Y., Pretorius, Lynette, Boey, Esther J. H., Lim, Lydia, Sadoshima, Junichi, Meikle, Peter J., Mellet, Natalie A., Woodcock, Elizabeth A., Marasco, Silvana, Ueyama, Tomomi, Du, Xiao-Jun, Febbraio, Mark A., McMullen, Julie R.
• Format: Article
• Language: English
• Subjects: 692/699/75/230; 692/699/75/29/1309; 692/700/565/1436; Animals; Atrial Fibrillation - drug therapy; Caveolin 1 - metabolism; Caveolin 3 - metabolism; Disease Models, Animal; Electrocardiography; G(M3) Ganglioside - metabolism; Heart Failure - prevention & control; HSP70 Heat-Shock Proteins - metabolism; Humanities and Social Sciences; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; Microarray Analysis; multidisciplinary; Oximes - chemistry; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Piperidines - chemistry; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - metabolism; Receptors, Somatomedin - metabolism; Risk Factors; Science; Science (multidisciplinary); Signal Transduction; Transgenes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6705

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. Atrial fibrillation and heart failure often coexist but are difficult to treat. Here the authors report a therapeutic strategy for atrial fibrillation and heart failure in mice, based on the activating effect of a small molecule, BGP-15, on IGF1 receptor signalling.