title: PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury.
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.
authors: Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Tomohisa
authors: T
authors: Nagoshi
authors: Takashi
authors: T
authors: Matsui
authors: Takuma
authors: T
authors: Aoyama
authors: Annarosa
authors: A
authors: Leri
authors: Piero
authors: P
authors: Anversa
authors: Ling
authors: L
authors: Li
authors: Wataru
authors: W
authors: Ogawa
authors: Federica
authors: F
authors: del Monte
authors: Judith K
authors: JK
authors: Gwathmey
authors: Luanda
authors: L
authors: Grazette
authors: Brian A
authors: BA
authors: Hemmings
authors: Brian
authors: B
authors: Hemmings
authors: David A
authors: DA
authors: Kass
authors: Hunter C
authors: HC
authors: Champion
authors: Anthony
authors: A
authors: Rosenzweig
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D020127:Recovery of Function / Q000235:genetics
chemical_list: D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C526292:IRS1 protein, human; C526295:Irs1 protein, mouse; C494918:AKT1 protein, human