A conserved role for phosphatidylinositol 3-kinase but not akt signaling in mitochondrial adaptations that accompany physiological cardiac hypertrophy
A conserved role for phosphatidylinositol 3-kinase but not akt signaling in mitochondrial adaptations that accompany physiological cardiac hypertrophy
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DOI：
10.1016/j.cmet.2007.09.001
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发表时间：
2007-10-01
期刊：
影响因子：
29
通讯作者：
Abel, E. Dale
中科院分区：
文献类型：
--
作者：
O'Neill, Brian T.;Kim, Jaetaek;Abel, E. Dale
生理性心脏肥大与线粒体适应相关，其特征在于PGC-Ia的活化和增加的脂肪酸氧化（FAO）能力。广泛认为，磷脂酰肌醇3-激酶（PI 3 K）信号传导至Akt 1是生理性心脏生长所必需的。然而，协调生理性肥大和代谢重塑的信号传导通路尚不完全清楚。我们在这里表明，PI 3 K的激活足以增加心肌FAO能力，尽管PGC-1 α的表达增加，但抑制PI 3 K信号传导可防止线粒体对生理性肥大刺激的适应。我们还表明，激活下游激酶Akt是不需要的线粒体适应，是次要的PI 3 K激活。因此，在生理性心脏生长中，PI 3 K是细胞生长和代谢重塑的整合剂。尽管PI 3 K信号传导至Akt 1是细胞生长所必需的，但Akt 1非依赖性途径介导伴随的线粒体适应。
Physiological cardiac hypertrophy is associated with mitochondrial adaptations that are characterized by activation of PGC-l alpha and increased fatty acid oxidative (FAO) capacity. It is widely accepted that phosphatidylinositol 3-kinase (PI3K) signaling to Akt1 is required for physiological cardiac growth. However, the signaling pathways that coordinate physiological hypertrophy and metabolic remodeling are incompletely understood. We show here that activation of PI3K is sufficient to increase myocardial FAO capacity and that inhibition of PI3K signaling prevents mitochondrial adaptations in response to physiological hypertrophic stimuli despite increased expression of PGC-1 alpha. We also show that activation of the downstream kinase Akt is not required for the mitochondrial adaptations that are secondary to PI3K activation. Thus, in physiological cardiac growth, PI3K is an integrator of cellular growth and metabolic remodeling. Although PI3K signaling to Akt1 is required for cellular growth, Akt-independent pathways mediate the accompanying mitochondrial adaptations.