title: The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice.
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.
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Geeta
authors.initials: G
authors.lastname: Sapra
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Yow Keat
authors.initials: YK
authors.lastname: Tham
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Nelly
authors.initials: N
authors.lastname: Cemerlang
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Aya
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Bernardo
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Darren C
authors.initials: DC
authors.lastname: Henstridge
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Jenny Y Y
authors.initials: JY
authors.lastname: Ooi
authors.affiliation: 1] Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia [2] Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Lynette
authors.initials: L
authors.lastname: Pretorius
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Esther J H
authors.initials: EJ
authors.lastname: Boey
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Lydia
authors.initials: L
authors.lastname: Lim
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, The State University of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Mellet
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Woodcock
authors.affiliation: Heart Centre, Alfred Hospital, Melbourne, Victoria 3004, Australia.
authors.forename: Silvana
authors.initials: S
authors.lastname: Marasco
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ueyama
authors.affiliation: Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.affiliation: 1] Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia [2] Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.affiliation: 1] Baker IDI Heart and Diabetes Institute, PO Box 6492, Melbourne, Victoria 3004, Australia [2] Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy*; D051242:Caveolin 1 / Q000378:metabolism; D051244:Caveolin 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D005679:G(M3) Ganglioside / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006333:Heart Failure / Q000517:prevention & control*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046228:Microarray Analysis; D010091:Oximes / Q000737:chemistry*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D019076:Transgenes
chemical_list: D051242:Caveolin 1; D051244:Caveolin 3; D005679:G(M3) Ganglioside; D018840:HSP70 Heat-Shock Proteins; C000597236:IGF1R protein, human; D010091:Oximes; D010880:Piperidines; D017451:Receptors, Somatomedin; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C405586:BGP 15