title: Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation.
abstract: 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.
authors.affiliation: Baker IDI Heart and Diabetes Institute, St. Kilda Rd. Central, Melbourne, Victoria 8008, Australia.
authors.forename: Lynette
authors.initials: L
authors.lastname: Pretorius
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Woodcock
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Ruby C Y
authors.initials: RC
authors.lastname: Lin
authors.forename: Silvana
authors.initials: S
authors.lastname: Marasco
authors.forename: Robert L
authors.initials: RL
authors.lastname: Medcalf
authors.forename: Ziqiu
authors.initials: Z
authors.lastname: Ming
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Head
authors.forename: Joon Win
authors.initials: JW
authors.lastname: Tan
authors.forename: Nelly
authors.initials: N
authors.lastname: Cemerlang
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shioi
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
authors.forename: Elena V
authors.initials: EV
authors.lastname: Lukoshkova
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Dart
authors.forename: Garry L
authors.initials: GL
authors.lastname: Jennings
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
mesh_terms: 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*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases
references.citation: J Clin Invest. 2003 May;111(10):1463-74
references.pmid: 12750396
references.citation: Prog Cardiovasc Dis. 2006 Jan-Feb;48(4):256-69
references.pmid: 16517247
references.citation: Circulation. 1999 Mar 23;99(11):1508-15
references.pmid: 10086977
references.citation: JAMA. 1994 Mar 16;271(11):840-4
references.pmid: 8114238
references.citation: J Clin Invest. 2006 Jun;116(6):1547-60
references.pmid: 16741575
references.citation: J Cardiovasc Electrophysiol. 2000 Jun;11(6):626-33
references.pmid: 10868735
references.citation: J Am Coll Cardiol. 2007 Jul 24;50(4):359-67
references.pmid: 17659204
references.citation: Cell. 2008 Dec 12;135(6):1017-27
references.pmid: 19070573
references.citation: Hypertension. 2005 Aug;46(2):412-8
references.pmid: 15967869
references.citation: Ann Oncol. 2009 Jun;20(6):1026-31
references.pmid: 19179558
references.citation: J Hypertens. 2004 Nov;22(11):2075-85
references.pmid: 15480090
references.citation: Cell Stress Chaperones. 2007 Summer;12(2):97-100
references.pmid: 17688187
references.citation: Ann Thorac Surg. 2005 Mar;79(3):865-71; discussion 871
references.pmid: 15734396
references.citation: Mol Cell Biol. 2008 May;28(10):3424-36
references.pmid: 18332105
references.citation: Cardiovasc Res. 2000 Dec;48(3):448-54
references.pmid: 11090840
references.citation: Am J Med. 2006 May;119(5):448.e1-19
references.pmid: 16651058
references.citation: Circulation. 1996 Aug 1;94(3):390-7
references.pmid: 8759081
references.citation: J Exp Med. 1978 Jul 1;148(1):223-34
references.pmid: 78958
references.citation: J Clin Invest. 2000 Aug;106(4):473-81
references.pmid: 10953022
references.citation: Circulation. 1998 Sep 8;98(10):946-52
references.pmid: 9737513
references.citation: Cardiovasc Res. 2006 Jun 1;70(3):543-54
references.pmid: 16631626
references.citation: FASEB J. 2003 Sep;17(12):1592-608
references.pmid: 12958166
references.citation: Circ Res. 2007 May 25;100(10):1415-27
references.pmid: 17525381
references.citation: J Clin Invest. 1983 Jun;71(6):1523-35
references.pmid: 6345584
references.citation: J Biol Chem. 2004 Feb 6;279(6):4782-93
references.pmid: 14597618
references.citation: J Clin Invest. 1999 Jun;103(12):1627-34
references.pmid: 10377168
references.citation: Stroke. 2003 Feb;34(2):537-43
references.pmid: 12574572
references.citation: Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1456-67
references.pmid: 15923312
references.citation: Cardiology. 2008;110(1):45-52
references.pmid: 17934269
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12355-60
references.pmid: 14507992
references.citation: Cardiovasc Surg. 2002 Jun;10(3):228-32
references.pmid: 12044430
references.citation: Nature. 2002 Jan 10;415(6868):219-26
references.pmid: 11805846
references.citation: Circulation. 2001 Jul 10;104(2):174-80
references.pmid: 11447082
references.citation: Am J Pathol. 2004 Sep;165(3):1019-32
references.pmid: 15331425
references.citation: JAMA. 2004 Nov 24;292(20):2471-7
references.pmid: 15562125
references.citation: Diabetes. 2005 Aug;54(8):2360-4
references.pmid: 16046302
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):612-7
references.pmid: 17202264
references.citation: J Am Coll Cardiol. 2008 Jul 22;52(4):241-50
references.pmid: 18634977
references.citation: Circ Res. 1999 Apr 16;84(7):776-84
references.pmid: 10205145
references.citation: J Am Coll Cardiol. 2001 Oct;38(4):1231-66
references.pmid: 11583910
references.citation: Anesth Analg. 2004 Feb;98(2):303-310
references.pmid: 14742359
references.citation: EMBO J. 2000 Jun 1;19(11):2537-48
references.pmid: 10835352
references.citation: Clin Exp Pharmacol Physiol. 2007 Apr;34(4):255-62
references.pmid: 17324134
references.citation: Cancer Cell. 2006 May;9(5):341-9
references.pmid: 16697955
references.citation: Physiol Rev. 2007 Oct;87(4):1285-342
references.pmid: 17928585
references.citation: Circulation. 2004 Jun 22;109(24):3050-5
references.pmid: 15184287
references.citation: Int J Cardiol. 2005 Dec 7;105(3):319-21
references.pmid: 16274776
references.citation: Cell Metab. 2007 Oct;6(4):294-306
references.pmid: 17908558
references.citation: Circulation. 2000 Jan 4-11;101(1):71-7
references.pmid: 10618307
references.citation: J Am Coll Cardiol. 2004 Dec 7;44(11):2117-24
references.pmid: 15582307
references.citation: Lancet. 2007 Aug 18;370(9587):604-18
references.pmid: 17707756
references.citation: J Am Coll Cardiol. 2003 Jul 16;42(2):336-44
references.pmid: 12875773
references.citation: Cell Cycle. 2007 Apr 15;6(8):910-3
references.pmid: 17404510
references.citation: Cardiovasc Res. 2000 Sep;47(4):788-96
references.pmid: 10974227
references.citation: J Am Coll Cardiol. 2006 Jan 3;47(1):9-21
references.pmid: 16386658
references.citation: Nature. 2006 May 18;441(7091):366-70
references.pmid: 16625210
references.citation: Circ Res. 2005 Jul 8;97(1):62-9
references.pmid: 15947250
references.citation: J Am Coll Cardiol. 2001 Mar 1;37(3):926-32
references.pmid: 11693772