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


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.
Lin
Ruby C Y
RC
Ramaciotti Centre for Gene Function Analysis, University of New South Wales, Randwick, Australia.
Weeks
Kate L
KL
Gao
Xiao-Ming
XM
Williams
Rohan B H
RB
Bernardo
Bianca C
BC
Kiriazis
Helen
H
Matthews
Vance B
VB
Woodcock
Elizabeth A
EA
Bouwman
Russell D
RD
Mollica
Janelle P
JP
Speirs
Helen J
HJ
Dawes
Ian W
IW
Daly
Roger J
RJ
Shioi
Tetsuo
T
Izumo
Seigo
S
Febbraio
Mark A
MA
Du
Xiao-Jun
XJ
McMullen
Julie R
JR
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
D048868:Adaptor Proteins, Signal Transducing; D058534:Class I Phosphatidylinositol 3-Kinases; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D012333:RNA, Messenger; C490977:Grb14 protein, mouse; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse