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首页> 外文期刊>The FASEB Journal >A PP2A-mediated feedback mechanism controls Ca 2+-dependent NO synthesis under physiological oxygen
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A PP2A-mediated feedback mechanism controls Ca 2+-dependent NO synthesis under physiological oxygen

机译：PP2A介导的反馈机制控制CA 2 + - 在生理氧气下没有合成

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Intracellular O_(2)is a key regulator of NO signaling, yet most in vitro studies are conducted in atmospheric O_(2)levels, hyperoxic with respect to the physiologic milieu. We investigated NO signaling in endothelial cells cultured in physiologic (5%) O_(2)and stimulated with histamine or shear stress. Culture of cells in 5% O_(2)(>5 d) decreased histamine- but not shear stress–stimulated endothelial (e)NOS activity. Unlike cells adapted to a hypoxic environment (1% O_(2)), those cultured in 5% O_(2)still mobilized sufficient Ca~(2+)to activate AMPK. Enhanced expression and membrane targeting of PP2A-C was observed in 5% O_(2), resulting in greater interaction with eNOS in response to histamine. Moreover, increased dephosphorylation of eNOS in 5% O_(2)was Ca~(2+)-sensitive and reversed by okadaic acid or PP2A-C siRNA. The present findings establish that Ca~(2+)mobilization stimulates both NO synthesis and PP2A-mediated eNOS dephosphorylation, thus constituting a novel negative feedback mechanism regulating eNOS activity not present in response to shear stress. This, coupled with enhanced NO bioavailability, underpins differences in NO signaling induced by inflammatory and physiologic stimuli that are apparent only in physiologic O_(2)levels. Furthermore, an explicit delineation between physiologic normoxia and genuine hypoxia is defined here, with implications for our understanding of pathophysiological hypoxia.—Keeley, T. P., Siow, R. C. M., Jacob, R., Mann, G. E. A PP2A-mediated feedback mechanism controls Ca~(2+)-dependent NO synthesis under physiological oxygen.
机译：细胞内O_（2）是NO信号的关键调节器，但大多数体外研究是在大气o_（2）水平，相对于生理环境中的过氧化症进行过氧化物。我们研究了在生理学（5％）O_（2）中培养的内皮细胞中的信号传导，并用组胺或剪切应力刺激。 5％O_（2）（> 5d）中细胞培养减少组胺 - 但不剪切应激刺激的内皮（E）NOS活性。与适应于缺氧环境的细胞（1％O_（2）），在5％O_（2）中培养的那些仍可动集足够的Ca〜（2+）以激活安培。在5％O_（2）中观察到PP2A-C的增强的表达和膜靶向，导致响应于组胺的与enos相互作用。此外，在5％O_（2）中增加了eNOS的去磷酸化是Ca〜（2 +） - 敏感，并被冈卡酸或PP2A-C siRNA逆转。本研究结果确定了Ca〜（2+）动员刺激无合成和PP2A介导的enos去磷酸化，从而构成新的负反馈机制调节eNOS活性的eNOS活性以响应剪切应力而不存在。这将加上增强的生物利用度，炎症和生理刺激诱导的信号传导的差异仅在生理o_（2）水平中。此外，这里定义了生理常氧和真正的缺氧之间的显式描绘，对我们对病理生理学缺氧的理解有影响。-Keeley，TP，Siow，RCM，jacob，R.，Mann，Ge A PP2A介导的反馈机制控制CA〜 （2 +） - 在生理氧中没有依赖于合成。

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