Adenosine kinase regulation of cardiomyocyte hypertrophy
Adenosine kinase regulation of cardiomyocyte hypertrophy
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DOI：
10.1152/ajpheart.00684.2010
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发表时间：
2011-05-01
影响因子：
4.8
通讯作者：
Bache, Robert J.
中科院分区：
文献类型：
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作者：
Fassett, John T.;Hu, Xinli;Bache, Robert J.
法西特JT，胡旭，徐翔，陆正，张平，陈勇，巴赫RJ。腺苷激酶对心肌细胞肥大的调节作用。Am J Physiol心脏圈Physiol300：H1722-H1732,2011年2月18日首次发布200DOI：10.1152/ajpheart.00684.2010-有证据表明细胞外腺苷可以减轻心肌肥厚。但这种情况发生的机制尚不清楚。在这里，我们研究了腺苷受体和腺苷代谢在减轻心肌细胞肥大中的作用。苯肾上腺素(PE)引起新生大鼠心肌细胞肥大，细胞表面积增加，蛋白质合成增加，心钠素(ANP)表达增加。这些反应可被5 mU M2-氯腺苷(CADO；腺苷脱氨酶抗性腺苷类似物)或10 mU M腺苷减弱。虽然腺苷受体的拮抗作用部分阻断了CAD引起的ANP表达的减少，但不能恢复细胞大小或蛋白质合成。支持细胞内腺苷代谢在调节肥大中的作用。腺苷激酶(AK)抑制剂碘结节杀菌素和ABT-702完全逆转了细胞大小和蛋白质合成的衰减。CADO或ADO表达ANP。PE诱导的磷酸化信号通路检测显示，Tado处理不降低AKT(Ser473)的磷酸化，但减弱Raf(Ser338)(Ser338)(24-48 h)、mTOR(Ser2448)(24-48 h)、p70S6K(Thr389)(2.5-48 h)和ERKThr202/Tyr204(48 H)的持续磷酸化。在CADO存在的情况下，抑制AK可恢复这些酶的激活。利用显性负性和结构性活性的Raf腺病毒，我们发现Raf的激活是PE诱导的mTORC1信号转导和心肌细胞肥大的必要条件和充分条件。然而，尽管ERKThr202/Tyr204和AKT(Ser473)有高水平的磷酸化，CADO处理仍然阻止了p70S6K(Thr389)的磷酸化和Raf下游的肥大。抑制AK可逆转CADO抑制Raf诱导的p70S6K(Thr389)磷酸化和肥大。综上所述，这些结果证实AK是腺苷抑制心肌细胞肥大的重要介质，它至少部分地通过抑制Raf信号转导mTOR/p70S6K而起作用。
Fassett JT, Hu X, Xu X, Lu Z, Zhang P, Chen Y, Bache RJ. Adenosine kinase regulation of cardiomyocyte hypertrophy. Am J Physiol Heart Circ Physiol 300: H1722-H1732, 2011 First published February 18, 200 doi:10.1152/ajpheart.00684.2010.-There is evidence that extracellular adenosine can attenuate cardiac hypertrophy. but the mechanism by which this occurs is not clear. Here we investigated the role of adenosine receptors and adenosine metabolism in attenuation of cardiomyocyte hypertrophy. Phenylephrine (PE) caused hypertrophy of neonatal rat cardiomyocytes with increases of cell surface area, protein synthesis, and atrial natriuretic peptide (ANP) expression. These responses were attenuated by 5 mu M 2-chloroadenosine (CADO; adenosine deaminase resistant adenosine analog) or 10 mu M adenosine. While antagonism of adenosine receptors partially blocked the reduction of ANP expression produced by CAD, it did not restore cell size or protein synthesis. In support of a role for intracellular adenosine metabolism in regulating hypertrophy. the adenosine kinase (AK) inhibitors iodotubercidin and ABT-702 completely reversed the attenuation of cell size, protein synthesis. and expression of ANP by CADO or ADO. Examination of PE-induced phosphosignaling pathways revealed that (TADO treatment did not reduce AKT(Ser473) phosphorylation but did attenuate sustained phosphorylation of Raf(Ser338) (24-48 h), mTOR(Ser2448) (24-48 h), p70S6k(Thr389) (2.5-48 h), and ERKThr202/Tyr204 (48 h). Inhibition of AK restored activation of these enzymes in the presence of CADO. Using dominant negative and constitutively active Raf adenoviruses, we found that Raf activation is necessary and sufficient for PE-induced mTORC1 signaling and cardiomyocyte hypertrophy. CADO treatment still blocked p70S6k(Thr389) phosphorylation and hypertrophy downstream of constitutively active Raf, however, despite a high level phosphorylation of ERKThr202/Tyr204 and AKT(Ser473). Reduction of Raf-induced p70S6k(Thr389) phosphorylation and hypertrophy by CADO was reversed by inhibiting AK. Together, these results identify AK as an important mediator of adenosine attenuation of cardiomyocyte hypertrophy, which acts, at least in part, through inhibition of Raf signaling to mTOR/p70S6k.