PI3K(p110α) protects against myocardial infarction-induced heart failure: Identification of PI3K-regulated miRNA and mRNA

Ruby C.Y. Lin; Kate L. Weeks; Xiao Ming Gao; Rohan B.H. Williams; Bianca C. Bernardo; Helen Kiriazis; Vance B. Matthews; Elizabeth A. Woodcock; Russell D. Bouwman; Janelle P. Mollica; Helen J. Speirs; Ian W. Dawes; Roger J. Daly; Tetsuo Shioi; Seigo Izumo; Mark A. Febbraio; Xiao Jun Du; Julie R. McMullen

doi:10.1161/ATVBAHA.109.201988

PI3K(p110α) protects against myocardial infarction-induced heart failure: Identification of PI3K-regulated miRNA and mRNA

Ruby C.Y. Lin, Kate L. Weeks, Xiao Ming Gao, Rohan B.H. Williams, Bianca C. Bernardo, Helen Kiriazis, Vance B. Matthews, Elizabeth A. Woodcock, Russell D. Bouwman, Janelle P. Mollica, Helen J. Speirs, Ian W. Dawes, Roger J. Daly, Tetsuo Shioi, Seigo Izumo, Mark A. Febbraio, Xiao Jun Du, Julie R. McMullen

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Abstract

Objective: Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110α)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110α) provides protection in a setting of MI is unknown, and PI3K(p110α) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110α) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110α). Methods and results: Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110α) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110α) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. Conclusion: Activation of PI3K(p110α) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110α) represent new drug targets for heart failure.

Original language	English
Pages (from-to)	724-732
Number of pages	9
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
Volume	30
Issue number	4
DOIs	https://doi.org/10.1161/ATVBAHA.109.201988
Publication status	Published - Apr 2010

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Lin, R. C. Y., Weeks, K. L., Gao, X. M., Williams, R. B. H., Bernardo, B. C., Kiriazis, H., Matthews, V. B., Woodcock, E. A., Bouwman, R. D., Mollica, J. P., Speirs, H. J., Dawes, I. W., Daly, R. J., Shioi, T., Izumo, S., Febbraio, M. A., Du, X. J., & McMullen, J. R. (2010). PI3K(p110α) protects against myocardial infarction-induced heart failure: Identification of PI3K-regulated miRNA and mRNA. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(4), 724-732. https://doi.org/10.1161/ATVBAHA.109.201988

@article{51c84353e5d9458aa40aa6b56cedb2e1,

title = "PI3K(p110α) protects against myocardial infarction-induced heart failure: Identification of PI3K-regulated miRNA and mRNA",

abstract = "Objective: Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110α)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110α) provides protection in a setting of MI is unknown, and PI3K(p110α) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110α) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110α). Methods and results: Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110α) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110α) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. Conclusion: Activation of PI3K(p110α) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110α) represent new drug targets for heart failure.",

author = "Lin, {Ruby C.Y.} and Weeks, {Kate L.} and Gao, {Xiao Ming} and Williams, {Rohan B.H.} and Bernardo, {Bianca C.} and Helen Kiriazis and Matthews, {Vance B.} and Woodcock, {Elizabeth A.} and Bouwman, {Russell D.} and Mollica, {Janelle P.} and Speirs, {Helen J.} and Dawes, {Ian W.} and Daly, {Roger J.} and Tetsuo Shioi and Seigo Izumo and Febbraio, {Mark A.} and Du, {Xiao Jun} and McMullen, {Julie R.}",

year = "2010",

month = apr,

doi = "10.1161/ATVBAHA.109.201988",

language = "English",

volume = "30",

pages = "724--732",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "4",

}

Lin, RCY, Weeks, KL, Gao, XM, Williams, RBH, Bernardo, BC, Kiriazis, H, Matthews, VB, Woodcock, EA, Bouwman, RD, Mollica, JP, Speirs, HJ, Dawes, IW, Daly, RJ, Shioi, T, Izumo, S, Febbraio, MA, Du, XJ & McMullen, JR 2010, 'PI3K(p110α) protects against myocardial infarction-induced heart failure: Identification of PI3K-regulated miRNA and mRNA', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 4, pp. 724-732. https://doi.org/10.1161/ATVBAHA.109.201988

TY - JOUR

T1 - PI3K(p110α) protects against myocardial infarction-induced heart failure

T2 - Identification of PI3K-regulated miRNA and mRNA

AU - Lin, Ruby C.Y.

AU - Weeks, Kate L.

AU - Gao, Xiao Ming

AU - Williams, Rohan B.H.

AU - Bernardo, Bianca C.

AU - Kiriazis, Helen

AU - Matthews, Vance B.

AU - Woodcock, Elizabeth A.

AU - Bouwman, Russell D.

AU - Mollica, Janelle P.

AU - Speirs, Helen J.

AU - Dawes, Ian W.

AU - Daly, Roger J.

AU - Shioi, Tetsuo

AU - Izumo, Seigo

AU - Febbraio, Mark A.

AU - Du, Xiao Jun

AU - McMullen, Julie R.

PY - 2010/4

Y1 - 2010/4

N2 - Objective: Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110α)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110α) provides protection in a setting of MI is unknown, and PI3K(p110α) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110α) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110α). Methods and results: Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110α) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110α) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. Conclusion: Activation of PI3K(p110α) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110α) represent new drug targets for heart failure.

AB - Objective: Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110α)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110α) provides protection in a setting of MI is unknown, and PI3K(p110α) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110α) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110α). Methods and results: Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110α) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110α) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. Conclusion: Activation of PI3K(p110α) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110α) represent new drug targets for heart failure.

UR - http://www.scopus.com/inward/record.url?scp=77950871530&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.109.201988

DO - 10.1161/ATVBAHA.109.201988

M3 - Article

SN - 1079-5642

VL - 30

SP - 724

EP - 732

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 4

ER -

PI3K(p110α) protects against myocardial infarction-induced heart failure: Identification of PI3K-regulated miRNA and mRNA

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