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

Cite this

Sapra, G., Tham, Y. K., Cemerlang, N., Matsumoto, A., Kiriazis, H., Bernardo, B. C., ... McMullen, J. R. (2014). The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. Nature Communications, 5, 1 - 16. [5705]. https://doi.org/10.1038/ncomms6705
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 ; Mellett, Natalie A ; Woodcock, Elizabeth A ; Marasco, Silvana ; Ueyama, Tomomi ; Du, Xiao-Jun ; Febbraio, Mark A ; McMullen, Julie R. / The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. In: Nature Communications. 2014 ; Vol. 5. pp. 1 - 16.
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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.",
author = "Geeta Sapra and Tham, {Yow Keat} and Nelly Cemerlang and Aya Matsumoto and Helen Kiriazis and Bernardo, {Bianca C} and Henstridge, {Darren C} and Ooi, {Jenny Y Y} and Lynette Pretorius and Boey, {Esther J H} and Lydia Lim and Junichi Sadoshima and Meikle, {Peter J} and Mellett, {Natalie A} and Woodcock, {Elizabeth A} and Silvana Marasco and Tomomi Ueyama and Xiao-Jun Du and Febbraio, {Mark A} and McMullen, {Julie R}",
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Sapra, G, Tham, YK, Cemerlang, N, Matsumoto, A, Kiriazis, H, Bernardo, BC, Henstridge, DC, Ooi, JYY, Pretorius, L, Boey, EJH, Lim, L, Sadoshima, J, Meikle, PJ, Mellett, NA, Woodcock, EA, Marasco, S, Ueyama, T, Du, X-J, Febbraio, MA & McMullen, JR 2014, 'The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice', Nature Communications, vol. 5, 5705, pp. 1 - 16. https://doi.org/10.1038/ncomms6705

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. / 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; Mellett, Natalie A; Woodcock, Elizabeth A; Marasco, Silvana; Ueyama, Tomomi; Du, Xiao-Jun; Febbraio, Mark A; McMullen, Julie R.

In: Nature Communications, Vol. 5, 5705, 2014, p. 1 - 16.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

AU - Sapra, Geeta

AU - Tham, Yow Keat

AU - Cemerlang, Nelly

AU - Matsumoto, Aya

AU - Kiriazis, Helen

AU - Bernardo, Bianca C

AU - Henstridge, Darren C

AU - Ooi, Jenny Y Y

AU - Pretorius, Lynette

AU - Boey, Esther J H

AU - Lim, Lydia

AU - Sadoshima, Junichi

AU - Meikle, Peter J

AU - Mellett, Natalie A

AU - Woodcock, Elizabeth A

AU - Marasco, Silvana

AU - Ueyama, Tomomi

AU - Du, Xiao-Jun

AU - Febbraio, Mark A

AU - McMullen, Julie R

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.nature.com/ncomms/2014/141209/ncomms6705/pdf/ncomms6705.pdf

U2 - 10.1038/ncomms6705

DO - 10.1038/ncomms6705

M3 - Article

VL - 5

SP - 1

EP - 16

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 5705

ER -

Sapra G, Tham YK, Cemerlang N, Matsumoto A, Kiriazis H, Bernardo BC et al. The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. Nature Communications. 2014;5:1 - 16. 5705. https://doi.org/10.1038/ncomms6705