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. Mellet, Elizabeth A. Woodcock, Silvana Marasco, Tomomi Ueyama, Xiao-Jun Du, Mark A. Febbraio () and Julie R. McMullen ()
Additional contact information
Geeta Sapra: Baker IDI Heart and Diabetes Institute, PO Box 6492
Yow Keat Tham: Baker IDI Heart and Diabetes Institute, PO Box 6492
Nelly Cemerlang: Baker IDI Heart and Diabetes Institute, PO Box 6492
Aya Matsumoto: Baker IDI Heart and Diabetes Institute, PO Box 6492
Helen Kiriazis: Baker IDI Heart and Diabetes Institute, PO Box 6492
Bianca C. Bernardo: Baker IDI Heart and Diabetes Institute, PO Box 6492
Darren C. Henstridge: Baker IDI Heart and Diabetes Institute, PO Box 6492
Jenny Y. Y. Ooi: Baker IDI Heart and Diabetes Institute, PO Box 6492
Lynette Pretorius: Baker IDI Heart and Diabetes Institute, PO Box 6492
Esther J. H. Boey: Baker IDI Heart and Diabetes Institute, PO Box 6492
Lydia Lim: Baker IDI Heart and Diabetes Institute, PO Box 6492
Junichi Sadoshima: Rutgers New Jersey Medical School, The State University of New Jersey
Peter J. Meikle: Baker IDI Heart and Diabetes Institute, PO Box 6492
Natalie A. Mellet: Baker IDI Heart and Diabetes Institute, PO Box 6492
Elizabeth A. Woodcock: Baker IDI Heart and Diabetes Institute, PO Box 6492
Silvana Marasco: Heart Centre, Alfred Hospital
Tomomi Ueyama: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Xiao-Jun Du: Baker IDI Heart and Diabetes Institute, PO Box 6492
Mark A. Febbraio: Baker IDI Heart and Diabetes Institute, PO Box 6492
Julie R. McMullen: Baker IDI Heart and Diabetes Institute, PO Box 6492

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6705

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