Home LiteratureArticle Details
PMID: 16007268 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury.

The Journal of clinical investigation ·Vol. 115 ·No. 8 ·2005-08-00 ·Pages 2128-38

Nagoshi T, Matsui T, Aoyama T, Leri A, Anversa P, Li L, Ogawa W, del Monte F, Gwathmey JK, Grazette L, Hemmings BA, Hemmings B, Kass DA, Champion HC, Rosenzweig A

Abstract

Acute activation of the serine-threonine kinase Akt is cardioprotective and reduces both infarction and dysfunction after ischemia/reperfusion injury (IRI). However, less is known about the chronic effects of Akt activation in the heart, and, paradoxically, Akt is activated in samples from patients with chronic heart failure. We generated Tg mice with cardiac-specific expression of either activated (myristoylated [myr]) or dominant-negative (dn) Akt and assessed their response to IRI in an ex vivo model. While dn-Akt hearts demonstrated a moderate reduction in functional recovery after IRI, no function was restored in any of the myr-Akt-Tg hearts. Moreover, infarcts were dramatically larger in myr-Akt-Tg hearts. Biochemical analyses demonstrated that chronic Akt activation induces feedback inhibition of PI3K activity through both proteasome-dependent degradation of insulin receptor substrate-1 (IRS-1) and inhibition of transcription of IRS-1 as well as that of IRS-2. To test the functional significance of these signaling changes, we performed in vivo cardiac gene transfer with constitutively active PI3K in myr-Akt-Tg mice. Restoration of PI3K rescued function and reduced injury after IRI. These data demonstrate that PI3K-dependent but Akt-independent effectors are required for full cardioprotection and suggest a mechanism by which chronic Akt activation can become maladaptive.

MeSH Terms
Animals Enzyme Activation/genetics Gene Expression Regulation/genetics Genes, Dominant/genetics Humans Insulin Receptor Substrate Proteins Mice Mice, Transgenic Myocardial Reperfusion Injury/enzymology,genetics Phosphatidylinositol 3-Kinases/metabolism Phosphoproteins/metabolism Proteasome Endopeptidase Complex/metabolism Protein Processing, Post-Translational/genetics Protein Serine-Threonine Kinases/genetics,metabolism Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-akt Recovery of Function/genetics
Chemicals
IRS1 protein, human Insulin Receptor Substrate Proteins Irs1 protein, mouse Phosphoproteins Proto-Oncogene Proteins AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Proteasome Endopeptidase Complex
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Nagoshi Tomohisa
Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Matsui Takashi
Aoyama Takuma
Leri Annarosa
Anversa Piero
Li Ling
Ogawa Wataru
del Monte Federica
Gwathmey Judith K
Grazette Luanda
Hemmings Brian A
Hemmings Brian
Kass David A
Champion Hunter C
Rosenzweig Anthony
References (53)
53 references, click to expand
  1. Adenoviral gene transfer of activated phosphatidylinositol 3'-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro.
    Circulation. 1999 Dec 7;100(23):2373-9 PMID: 10587343
  2. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart.
    Circulation. 2000 Feb 15;101(6):660-7 PMID: 10673259
  3. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307).
    J Biol Chem. 2000 Mar 24;275(12):9047-54 PMID: 10722755
  4. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1.
    Mol Endocrinol. 2000 Jun;14(6):783-94 PMID: 10847581
  5. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C.
    Circ Res. 2000 Aug 18;87(4):309-15 PMID: 10948065
  6. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure.
    Circulation. 2001 Feb 6;103(5):670-7 PMID: 11156878
  7. Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes.
    Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3756-61 PMID: 11259670
  8. Reperfusion-activated Akt kinase prevents apoptosis in transgenic mouse hearts overexpressing insulin-like growth factor-1.
    Circ Res. 2001 Mar 30;88(6):609-14 PMID: 11282895
  9. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo.
    Circulation. 2001 Jul 17;104(3):330-5 PMID: 11457753
  10. Prevention of fat-induced insulin resistance by salicylate.
    J Clin Invest. 2001 Aug;108(3):437-46 PMID: 11489937
  11. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling.
    Circ Res. 2001 Dec 7;89(12):1191-8 PMID: 11739285
  12. Molecular mechanism of insulin-induced degradation of insulin receptor substrate 1.
    Mol Cell Biol. 2002 Feb;22(4):1016-26 PMID: 11809794
  13. Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective.
    Circ Res. 2002 Mar 8;90(4):377-9 PMID: 11884365
  14. The phosphoinositide 3-kinase pathway.
    Science. 2002 May 31;296(5573):1655-7 PMID: 12040186
  15. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart.
    J Biol Chem. 2002 Jun 21;277(25):22896-901 PMID: 11943770
  16. Transcriptional effects of chronic Akt activation in the heart.
    J Biol Chem. 2002 Jun 21;277(25):22528-33 PMID: 11956204
  17. Inflammatory mediators and the failing heart: past, present, and the foreseeable future.
    Circ Res. 2002 Nov 29;91(11):988-98 PMID: 12456484
  18. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex.
    J Biol Chem. 2002 Dec 13;277(50):48115-21 PMID: 12351658
  19. Signaling pathways activated by vasoactive peptides in the cardiac myocyte and their role in myocardial pathologies.
    J Card Fail. 2002 Dec;8(6 Suppl):S359-69 PMID: 12555146
  20. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome.
    J Biol Chem. 2003 Apr 4;278(14):12361-6 PMID: 12517744
  21. Strategic advantages of insulin-like growth factor-I expression for cardioprotection.
    J Gene Med. 2003 Apr;5(4):277-86 PMID: 12692862
  22. Protein kinase B alpha/Akt1 regulates placental development and fetal growth.
    J Biol Chem. 2003 Aug 22;278(34):32124-31 PMID: 12783884
  23. Insulin down-regulates insulin receptor substrate-2 expression through the phosphatidylinositol 3-kinase/Akt pathway.
    J Endocrinol. 2003 Nov;179(2):253-66 PMID: 14596677
  24. Robust adenoviral and adeno-associated viral gene transfer to the in vivo murine heart: application to study of phospholamban physiology.
    Circulation. 2003 Dec 2;108(22):2790-7 PMID: 14638552
  25. Initial steps of insulin signaling and glucose transport are defective in the type 2 diabetic rat heart.
    Cardiovasc Res. 2004 Feb 1;61(2):288-96 PMID: 14736545
  26. In vitro phosphorylation of insulin receptor substrate 1 by protein kinase C-zeta: functional analysis and identification of novel phosphorylation sites.
    Biochemistry. 2004 May 18;43(19):5888-901 PMID: 15134463
  27. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore.
    J Clin Invest. 2004 Jun;113(11):1535-49 PMID: 15173880
  28. Protein kinase C-zeta-induced phosphorylation of Ser318 in insulin receptor substrate-1 (IRS-1) attenuates the interaction with the insulin receptor and the tyrosine phosphorylation of IRS-1.
    J Biol Chem. 2004 Jun 11;279(24):25157-63 PMID: 15069075
  29. Tissue-specific regulation of the alpha-myosin heavy chain gene promoter in transgenic mice.
    J Biol Chem. 1991 Dec 25;266(36):24613-20 PMID: 1722208
  30. Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum.
    Mol Cell Biol. 1993 Apr;13(4):2031-40 PMID: 8455596
  31. Local contractile and growth modulators in the myocardium.
    Clin Cardiol. 1993 May;16(5 Suppl 2):II5-9 PMID: 8504588
  32. The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential.
    Oncogene. 1993 Jul;8(7):1957-63 PMID: 8510938
  33. Cardioprotective actions of a monoclonal antibody against CD-18 in myocardial ischemia-reperfusion injury.
    Circulation. 1993 Oct;88(4 Pt 1):1779-87 PMID: 8104739
  34. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene.
    Nature. 1994 Nov 10;372(6502):186-90 PMID: 7526222
  35. Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion.
    Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8031-5 PMID: 7644533
  36. Identification by mutation of the tyrosine residues in the insulin receptor substrate-1 affecting association with the tyrosine phosphatase 2C and phosphatidylinositol 3-kinase.
    Endocrinology. 1995 Dec;136(12):5291-7 PMID: 7588273
  37. Nitric oxide attenuates neutrophil-mediated myocardial contractile dysfunction after ischemia and reperfusion.
    Circ Res. 1996 Jan;78(1):65-72 PMID: 8603507
  38. Characterization and regulation of the mouse insulin receptor substrate gene promoter.
    Mol Endocrinol. 1995 Oct;9(10):1367-79 PMID: 8544845
  39. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat. A combined in vivo and in vitro evaluation.
    Circulation. 1996 Feb 15;93(4):800-9 PMID: 8641010
  40. Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice.
    Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8630-5 PMID: 8710922
  41. Peroxynitrite inhibits leukocyte-endothelial cell interactions and protects against ischemia-reperfusion injury in rats.
    J Clin Invest. 1997 Feb 15;99(4):684-91 PMID: 9045871
  42. Expression of a constitutively active phosphatidylinositol 3-kinase induces process formation in rat PC12 cells. Use of Cre/loxP recombination system.
    J Biol Chem. 1997 Jun 27;272(26):16089-92 PMID: 9195902
  43. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy.
    J Clin Invest. 1997 Oct 15;100(8):1991-9 PMID: 9329962
  44. Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response.
    Circulation. 2005 Apr 5;111(13):1652-9 PMID: 15795328
  45. The PI3K-PDK1 connection: more than just a road to PKB.
    Biochem J. 2000 Mar 15;346 Pt 3:561-76 PMID: 10698680
  46. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation.
    Nature. 1999 Jun 10;399(6736):601-5 PMID: 10376603
  47. A simplified system for generating recombinant adenoviruses.
    Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2509-14 PMID: 9482916
  48. Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not of glucose transport.
    Mol Cell Biol. 1998 Jul;18(7):3708-17 PMID: 9632753
  49. Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated muscles.
    Circ Res. 1998 Jul 13;83(1):50-9 PMID: 9670918
  50. Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway.
    J Biol Chem. 1999 Apr 2;274(14):9351-6 PMID: 10092613
  51. Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats.
    Diabetes. 1999 Apr;48(4):801-12 PMID: 10102697
  52. Insulin-like growth factor-1 attenuates the detrimental impact of nonocclusive coronary artery constriction on the heart.
    Circ Res. 1999 May 14;84(9):1007-19 PMID: 10325238
  53. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt.
    Nature. 1999 Jun 10;399(6736):597-601 PMID: 10376602
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI23073
Published
2005-08-00
Epub
2005-00-07
Pages
2128-38
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1172227
Subset
IM
Grants
NCRR NIH HHS · RR-016362 · United States
NHLBI NIH HHS · HL-04250 · United States
NHLBI NIH HHS · R43 HL067516 · United States
NHLBI NIH HHS · R01 HL059521 · United States
NHLBI NIH HHS · HL-49574 · United States
NHLBI NIH HHS · K08 HL004250 · United States
NHLBI NIH HHS · HL-59521 · United States
NHLBI NIH HHS · HL-67516 · United States
NHLBI NIH HHS · R44 HL067516 · United States
Corrections
ErratumIn
-
CommentIn
PMID: 16075047
External Links
PubMed source DOI: 10.1172/JCI23073 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2