Muslin Anthony J, DeBosch Brian
Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Novartis Found Symp. 2006;274:118-26; discussion 126-31, 152-5, 272-6.
The Akt family of intracellular protein kinases regulates cellular growth, proliferation, survival and metabolism. Postnatal growth of the heart chiefly involves non-proliferative cardiac myocyte enlargement analogous to skeletal muscle growth. Cardiac hypertrophy exists in a 'physiological' form that is an adaptive response to long-term exercise training, and as a 'pathological' form that is often a maladaptive response to hypertension or valvular heart disease. By use of an Akt1-deficient mouse model system, we determined that Akt1 activity is required for physiologic cardiac growth in response to insulin-like growth factor 1 stimulation or exercise training. In contrast, Akt1 activity was found to antagonize pathologic cardiac growth that occurs in response to endothelin 1 stimulation or pressure overload. Evaluation of an Akt2-deficient mouse model system demonstrated that this family member plays an important role in insulin-stimulated glucose uptake and metabolism, and may not regulate physiologic or pathologic cardiac growth. Therefore, Akt1 selectively promotes physiological cardiac growth while Akt2 selectively promotes insulin-stimulated cardiac glucose metabolism.
细胞内蛋白激酶的Akt家族调节细胞生长、增殖、存活和代谢。出生后心脏的生长主要涉及类似于骨骼肌生长的非增殖性心肌细胞增大。心脏肥大以“生理性”形式存在，这是对长期运动训练的适应性反应，也以“病理性”形式存在，这通常是对高血压或瓣膜性心脏病的适应不良反应。通过使用Akt1缺陷小鼠模型系统，我们确定Akt1活性是胰岛素样生长因子1刺激或运动训练后生理性心脏生长所必需的。相反，发现Akt1活性拮抗内皮素1刺激或压力超负荷后发生的病理性心脏生长。对Akt2缺陷小鼠模型系统的评估表明，该家族成员在胰岛素刺激的葡萄糖摄取和代谢中起重要作用，可能不调节生理性或病理性心脏生长。因此，Akt1选择性促进生理性心脏生长，而Akt2选择性促进胰岛素刺激的心脏葡萄糖代谢。
