title: Pik3ip1 modulates cardiac hypertrophy by inhibiting PI3K pathway.
abstract: Cardiac hypertrophy is an adaptive response to various physiological and pathological stimuli. Phosphoinositide-3 kinase (PI3K) is a highly conserved lipid kinase involved in physiological cardiac hypertrophy (PHH). PI3K interacting protein1 (Pik3ip1) shares homology with the p85 regulatory subunit of PI3K and is known to interact with the p110 catalytic subunit of PI3K, leading to attenuation of PI3K activity in liver and immune cells. However, the role of Pik3ip1 in the heart remains unknown. In the present study, the effects of Pik3ip1 on cardiac hypertrophy were examined. We found that the expression level of Pik3ip1 was markedly higher in cardiomyocytes than in fibroblasts. The interaction of Pik3ip1 with the p110a subunit of PI3K in the heart was identified by immunoprecipitation using neonatal rat cardiomyocytes (NRCM). Approximately 35% knockdown of Pik3ip1 was sufficient to induce myocardial hypertrophy. Pik3ip1 deficiency was shown to lead to activation of PI3K/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) signaling pathway, increasing protein synthesis and cell size. However, adenovirus-mediated overexpression of Pik3ip1 attenuated PI3K-mediated cardiac hypertrophy. Pik3ip1 was upregulated by PHH due to swimming training, but not by pathological cardiac hypertrophy (PAH) due to pressure-overload, suggesting that Pik3ip1 plays a compensatory negative role for PHH. Collectively, our results elucidate the mechanisms for the roles of Pik3ip1 in PI3K/AKT signaling pathway.
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
authors.forename: Hong Ki
authors.initials: HK
authors.lastname: Song
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
authors.forename: Jong Sub
authors.initials: JS
authors.lastname: Lee
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
authors.forename: Kyoung Jin
authors.initials: KJ
authors.lastname: Nho
authors.affiliation: Department of Cardiology, Chonnam National University Hospital, Gwangju, Republic of Korea.
authors.forename: Hae Chang
authors.initials: HC
authors.lastname: Jeong
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
authors.forename: Jihwa
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Cardiology, Chonnam National University Hospital, Gwangju, Republic of Korea.
authors.forename: Youngkeun
authors.initials: Y
authors.lastname: Ahn
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
authors.forename: Do Han
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020868:Gene Silencing; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010805:Physical Conditioning, Animal; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; C579635:Pik3ip1 protein, mouse; D034741:RNA, Small Interfering; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
references.citation: J Pathol. 2003 Mar;199(3):387-97
references.pmid: 12579541
references.citation: Curr Pharm Des. 2011;17(18):1818-24
references.pmid: 21631421
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12355-60
references.pmid: 14507992
references.citation: Circulation. 2004 Apr 6;109(13):1580-9
references.pmid: 15066961
references.citation: Circulation. 2004 Jun 22;109(24):3050-5
references.pmid: 15184287
references.citation: Cardiovasc Res. 2004 Aug 15;63(3):403-13
references.pmid: 15276465
references.citation: Physiol Rev. 2011 Jul;91(3):1023-70
references.pmid: 21742795
references.citation: J Am Coll Cardiol. 2011 Jan 18;57(3):310-2
references.pmid: 21232668
references.citation: Cardiovasc Res. 2012 Jan 1;93(1):69-78
references.pmid: 22012952
references.citation: J Biol Chem. 2012 Mar 23;287(13):9827-34
references.pmid: 22228770
references.citation: PLoS One. 2012;7(4):e35552
references.pmid: 22523601
references.citation: Eur J Immunol. 2012 Oct;42(10):2754-9
references.pmid: 22706993
references.citation: Obes Rev. 2012 Dec;13 Suppl 2:58-68
references.pmid: 23107260
references.citation: FASEB J. 2012 Dec;26(12):4990-5001
references.pmid: 22935140
references.citation: Nat Rev Mol Cell Biol. 2013 Jan;14(1):38-48
references.pmid: 23258295
references.citation: J Clin Invest. 2013 Jan;123(1):37-45
references.pmid: 23281408
references.citation: Eur J Appl Physiol. 2013 Oct;113(10):2473-86
references.pmid: 23812090
references.citation: Biochem J. 2014 Jan 1;457(1):151-62
references.pmid: 24117217
references.citation: Nat Genet. 2014 Jan;46(1):33-8
references.pmid: 24316979
references.citation: Nat Rev Drug Discov. 2014 Feb;13(2):140-56
references.pmid: 24481312
references.citation: EMBO J. 2000 Jun 1;19(11):2537-48
references.pmid: 10835352
references.citation: Circulation. 2000 Jul 25;102(4):470-9
references.pmid: 10908222
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12333-8
references.pmid: 12237475
references.citation: Proc Natl Acad Sci U S A. 1988 Jan;85(2):339-43
references.pmid: 2963328
references.citation: N Engl J Med. 1999 Oct 21;341(17):1276-83
references.pmid: 10528039
references.citation: J Clin Invest. 2005 Aug;115(8):2059-64
references.pmid: 16075047
references.citation: J Clin Invest. 2005 Aug;115(8):2108-18
references.pmid: 16075055
references.citation: Mol Cell Biol. 2005 Nov;25(21):9491-502
references.pmid: 16227599
references.citation: Circulation. 2006 May 2;113(17):2097-104
references.pmid: 16636172
references.citation: Nat Rev Mol Cell Biol. 2006 Aug;7(8):589-600
references.pmid: 16936699
references.citation: Biochem Biophys Res Commun. 2007 Jun 22;358(1):66-72
references.pmid: 17475214
references.citation: Front Biosci. 2008;13:312-24
references.pmid: 17981549
references.citation: J Cell Physiol. 2008 Feb;214(2):316-21
references.pmid: 17941081
references.citation: Cancer Res. 2008 Jul 15;68(14):5591-8
references.pmid: 18632611
references.citation: Int J Biochem Cell Biol. 2008;40(10):2023-39
references.pmid: 18407781
references.citation: J Mol Cell Cardiol. 2008 Dec;45(6):796-803
references.pmid: 18929570
references.citation: Beijing Da Xue Xue Bao. 2008 Dec 18;40(6):572-7
references.pmid: 19088825
references.citation: Nature. 2008 Dec 18;456(7224):980-4
references.pmid: 19043405
references.citation: Heart Fail Clin. 2010 Jan;6(1):115-24
references.pmid: 19945067
references.citation: Pharmacol Res. 2010 Apr;61(4):269-80
references.pmid: 19969085
references.citation: Trends Pharmacol Sci. 2003 Jul;24(7):366-76
references.pmid: 12871670