Nuclear targeting of At antagonizes aspects of cardiomyocyte hypertrophy
Nuclear targeting of At antagonizes aspects of cardiomyocyte hypertrophy
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DOI：
10.1073/pnas.0510138103
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发表时间：
2006-08-08
影响因子：
11.1
通讯作者：
Sussman, Mark A.
中科院分区：
文献类型：
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作者：
Tsujita, Yasuyuki;Muraski, John;Sussman, Mark A.
丝氨酸/苏氨酸激酶Akt调节细胞存活、增殖、基因转录、蛋白质翻译、代谢和分化。虽然Akt底物遍布整个细胞，但激活的Akt通常在细胞核中积累，这表明生物学相关靶点位于那里。通过使用核靶向Akt（Akt-nuc）探索心肌细胞中核Akt信号传导的后果。Akt-nuc的积累并不引起肥大，不像组成性激活的Akt。相反，Akt-nuc抑制心肌肥厚，同时增加心房利钠肽（ANP）的表达，这取决于磷脂酰肌醇-3激酶的活性。Akt-nuc抗肥大作用通过抑制培养的心肌细胞中的鸟苷酸环化酶A受体或环磷酸鸟苷依赖性蛋白激酶来阻断。确证的证据显示，Akt-nuc转基因小鼠在横向主动脉缩窄后急性肥厚性重构减弱，与较高的ANP表达和较小的肌细胞体积一致。此外，Akt-nuc表达改善了横向主动脉缩窄诱导的肥厚慢性期的收缩功能和存活率。因此，Akt-nuc通过促进ANP表达的磷脂酰肌醇-3激酶依赖性信号级联的自分泌/旁分泌刺激拮抗肥大的某些方面，导致促存活与抗肥大信号的独特组合。
The serine/threonine kinase Akt regulates cellular survival, proliferation, gene transcription, protein translation, metabolism, and differentiation. Although Akt substrates are found throughout the cell, activated Akt normally accumulates in the nucleus, suggesting that biologically relevant targets are located there. Consequences of nuclear Akt signaling in cardiomyocytes were explored by using nuclear-targeted Akt (Akt-nuc). Accumulation of Akt-nuc did not provoke hypertrophy, unlike constitutively activated Akt. Instead, Akt-nuc inhibited hypertrophy concurrent with increased atrial natriuretic peptide (ANP) expression that depended upon phosphatidylinositol-3 kinase activity. Akt-nuc anti hypertrophic effects were blocked by inhibition of either guanylyl cyclase A receptor or cyclic guanosine monophosphate-dependent protein kinase in cultured cardiomyocytes. Corroborating evidence showed blunted acute hypertrophic remodeling in Akt-nuc transgenic mice after transverse aortic constriction coincident with higher ANP expression and smaller myocyte volume. In addition, Akt-nuc expression improved systolic function and survival in the chronic phase of transverse aortic constriction-induced hypertrophy. Thus, Akt-nuc antagonizes certain aspects of hypertrophy through autocrine/ paracrine stimulation of a phosphatidylinositol-3 kinase-dependent signaling cascade that promotes ANP expression, resulting in a unique combination of prosurvival coupled with antihypertrophic signaling.