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PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury
Tomohisa Nagoshi, … , Hunter C. Champion, Anthony Rosenzweig
Tomohisa Nagoshi, … , Hunter C. Champion, Anthony Rosenzweig
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2128-2138. https://doi.org/10.1172/JCI23073.
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Research Article Cardiology

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

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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

Tomohisa Nagoshi, Takashi Matsui, Takuma Aoyama, Annarosa Leri, Piero Anversa, Ling Li, Wataru Ogawa, Federica del Monte, Judith K. Gwathmey, Luanda Grazette, Brian Hemmings, David A. Kass, Hunter C. Champion, Anthony Rosenzweig

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Figure 1

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Chronic Akt activation in myr-Akt–Tg mice has detrimental effects on car...
Chronic Akt activation in myr-Akt–Tg mice has detrimental effects on cardiac functional recovery and injury after ischemia/reperfusion. (A) LVDP profiles during ischemia/reperfusion in NTg (filled squares; n = 11), myr-Akt (open circles; n = 11), and dn-Akt mice (filled triangles; n = 5). †P < 0.01 and ‡P < 0.001, myr-Akt versus NTg; *P < 0.001, dn-Akt versus NTg. (B) Maximum LVDP recovery (percent of baseline) measured at 40 minutes of reperfusion. ##P < 0.0001 versus NTg; **P < 0.02 versus NTg. (C) CPK values in the effluent collected during reperfusion period (NTg, n = 6; dn-Akt, n = 4; myr-Akt, n = 7). ***P < 0.02 versus dn-Akt. (D) Micrograph showing representative TTC staining of cardiac sections from NTg (top row) and myr-Akt (bottom row) mice. Effects on quantitated cumulative infarct area size in myr-Akt compared with NTg mice (n = 3 each) are represented in the bar graph. §P < 0.005 versus NTg. %MI, myocardial infarct area/ventricular area. (E) Representative DNA laddering indicating the degree of apoptosis in perfused heart tissues from myr-Akt and NTg mice (n = 3 each) after 20 minutes ischemia/40 minutes reperfusion (I/R40). Bar graphs depict quantitation of DNA ladder density and represent results of 3 independent experiments after 20 minutes of ischemia and either 5 (I/R5) or 40 minutes of reperfusion.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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