PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury
PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury
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DOI：
10.1172/jci23073
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发表时间：
2005-08-01
影响因子：
15.9
通讯作者：
Rosenzweig, A
中科院分区：
文献类型：
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作者：
Nagoshi, T;Matsui, T;Rosenzweig, A
丝氨酸-苏氨酸激酶Akt的急性激活具有心脏保护作用，可减少缺血/再灌注损伤（IRI）后的梗死和功能障碍。然而，对Akt激活在心脏中的慢性效应知之甚少，并且矛盾的是，Akt在慢性心力衰竭患者的样本中被激活。我们产生了心脏特异性表达激活（肉豆蔻酰化[myr]）或显性阴性（dn）Akt的Tg小鼠，并在离体模型中评估了它们对IRI的反应。虽然dn-Akt心脏显示IRI后功能恢复中度降低，但在任何myr-Akt-Tg心脏中均未恢复功能。此外，myr-Akt-Tg心脏中的梗死显著更大。生化分析表明，慢性Akt激活诱导反馈抑制PI 3 K活性通过蛋白酶体依赖性降解胰岛素受体底物-1（IRS-1）和抑制IRS-1以及IRS-2的转录。为了测试这些信号变化的功能意义，我们在myr-Akt-Tg小鼠中使用组成型活性PI 3 K进行了体内心脏基因转移。PI 3 K的恢复挽救了IRI后的功能并减少了损伤。这些数据表明，PI 3 K依赖性但Akt非依赖性效应器是完全心脏保护所必需的，并表明慢性Akt激活可能变得适应不良的机制。
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.