Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation.
Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110alpha) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110alpha) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult ( approximately 4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice ( approximately 15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF, suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110alpha) and AF.
Pretorius
Lynette
L
Baker IDI Heart and Diabetes Institute, St. Kilda Rd. Central, Melbourne, Victoria 8008, Australia.
Du
Xiao-Jun
XJ
Woodcock
Elizabeth A
EA
Kiriazis
Helen
H
Lin
Ruby C Y
RC
Marasco
Silvana
S
Medcalf
Robert L
RL
Ming
Ziqiu
Z
Head
Geoffrey A
GA
Tan
Joon Win
JW
Cemerlang
Nelly
N
Sadoshima
Junichi
J
Shioi
Tetsuo
T
Izumo
Seigo
S
Lukoshkova
Elena V
EV
Dart
Anthony M
AM
Jennings
Garry L
GL
McMullen
Julie R
JR
D000818:Animals; D001281:Atrial Fibrillation / Q000201:enzymology* / Q000209:etiology; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004789:Enzyme Activation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases
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