PI3K(p110 alpha) protects against myocardial infarction-induced heart failure: identification of PI3K-regulated miRNA and mRNA

Ruby CY Lin, Kate L Weeks, Xiao-Ming Gao, Rohan BH Williams, Bianca C Bernardo, Helen Kiriazis, Vance Matthews, Elizabeth A Woodcock, Russell Bouwman, Janelle Mollica, Helen J Speirs, Ian William Dawes, Roger John Daly, Tetsuo Shioi, Seigo Izumo, Mark Anthony Febbraio, Xiao-Jun Du, Julie Rae 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(p110 alpha)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110 alpha) provides protection in a setting of MI is unknown, and PI3K(p110 alpha) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110 alpha) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110 alpha). METHODS AND RESULTS: Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110 alpha) 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(p110 alpha) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. CONCLUSIONS: Activation of PI3K(p110 alpha) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110 alpha) represent new drug targets for heart failure.
Original languageEnglish
Pages (from-to)724 - 732
Number of pages9
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume30
Issue number4
DOIs
Publication statusPublished - 2010
Externally publishedYes

Cite this

Lin, R. CY., Weeks, K. L., Gao, X-M., Williams, R. BH., Bernardo, B. C., Kiriazis, H., Matthews, V., Woodcock, E. A., Bouwman, R., Mollica, J., Speirs, H. J., Dawes, I. W., Daly, R. J., Shioi, T., Izumo, S., Febbraio, M. A., Du, X-J., & McMullen, J. R. (2010). PI3K(p110 alpha) 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