Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase Cβ2 in the regulation of physiologic developmental hypertrophy and heart function
Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase Cβ2 in the regulation of physiologic developmental hypertrophy and heart function
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DOI：
10.1152/ajpheart.00562.2008
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发表时间：
2009-03-01
影响因子：
4.8
通讯作者：
Kang, Peter M.
中科院分区：
文献类型：
--
作者：
Rigor, Debra L.;Bodyak, Natalya;Kang, Peter M.
Rigor DL、Bodyak N、Bae S、Choi JH、Zhang L、Ter-Ovanesyan D、He Z、McMullen JR、Shioi T、Izumo S、King GL、Kang PM。磷酸肌醇 3-激酶 Akt 信号通路与蛋白激酶 C beta 2 相互作用，调节生理发育肥大和心脏功能。 Am J Physiol Heart Circ Physiol 296：H566-H572，2009。首次发表于 2009 年 1 月 2 日； doi:10.1152/ajpheart.00562.2008.-磷酸肌醇 3-激酶 (PI3-激酶)-蛋白激酶 B (Akt) 信号通路对于诱导生理性心脏肥大至关重要。相反，蛋白激酶 C beta 2 (PKC beta 2) 与病理性心脏肥大和心力衰竭的发展有关。到目前为止，尚未证明这两种途径之间存在明确的关联。在这项研究中，我们通过将转基因小鼠与心脏特异性表达 PKC beta 2、组成型活性 (ca) PI3-激酶和显性失活 (dn) PI3-激酶的转基因小鼠杂交，研究了 PI3-激酶和 PKC beta 2 通路之间的潜在相互作用。在caPI3激酶/PKCβ2和dnPI3激酶/PKCβ2双转基因小鼠中，心脏重量与体重之比和心肌细胞大小分别与caPI3激酶和dnPI3激酶转基因小鼠中观察到的相似，表明通过调节心肌细胞大小来调节生理性发育肥大是通过PI3激酶途径进行的。此外，我们观察到caPI3激酶/PKCβ2小鼠的心脏功能得到改善，而dnPI3激酶/PKCβ2小鼠的功能与PKCβ2组相似。 dnPI3-激酶/PKC β 2 和 PKC β 2 小鼠中的 PKC β 2 蛋白水平显着上调。然而有趣的是，在 caPI3 激酶/PKC β 2 小鼠中，PKC β 2 蛋白表达显着减弱。通过 Akt 磷酸化测量的 PI3 激酶活性不受 PKC beta 2 过表达的影响。这些数据表明心脏中这两条通路之间存在潜在的相互作用，其中 PI3 激酶主要负责生理性发育肥大的调节，并且可能作为 PKC beta 2 的上游调节剂，具有挽救由 PKC beta 过度表达引起的病理性心脏功能障碍的潜力。
Rigor DL, Bodyak N, Bae S, Choi JH, Zhang L, Ter-Ovanesyan D, He Z, McMullen JR, Shioi T, Izumo S, King GL, Kang PM. Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase C beta 2 in the regulation of physiologic developmental hypertrophy and heart function. Am J Physiol Heart Circ Physiol 296: H566-H572, 2009. First published January 2, 2009; doi:10.1152/ajpheart.00562.2008.-The phosphoinositide 3-kinase (PI3-kinase)-protein kinase B (Akt) signaling pathway is essential in the induction of physiological cardiac hypertrophy. In contrast, protein kinase C beta 2 (PKC beta 2) is implicated in the development of pathological cardiac hypertrophy and heart failure. Thus far, no clear association has been demonstrated between these two pathways. In this study, we examined the potential interaction between the PI3-kinase and PKC beta 2 pathways by crossing transgenic mice with cardiac specific expression of PKC beta 2, constitutively active (ca) PI3-kinase, and dominant-negative (dn) PI3-kinase. In caPI3-kinase/PKC beta 2 and dnPI3-kinase/PKC beta 2 double-transgenic mice, the heart weight-to-body weight ratios and cardiomyocyte sizes were similar to those observed in caPI3-kinase and dnPI3-kinase transgenic mice, respectively, suggesting that the regulation of physiological developmental hypertrophy via modulation of cardiomyocyte size proceeds through the PI3-kinase pathway. In addition, we observed that caPI3-kinase/PKC beta 2 mice showed improved cardiac function while the function of dnPI3-kinase/PKC beta 2 mice was similar to that of the PKC beta 2 group. PKC beta 2 protein levels in both dnPI3-kinase/PKC beta 2 and PKC beta 2 mice were significantly upregulated. Interestingly, however, PKC beta 2 protein expression was significantly attenuated in caPI3-kinase/PKC beta 2 mice. PI3-kinase activity measured by Akt phosphorylation was not affected by PKC beta 2 overexpression. These data suggest a potential interaction between these two pathways in the heart, where PI3-kinase is predominantly responsible for the regulation of physiological developmental hypertrophy and may act as an upstream modulator of PKC beta 2 with the potential for rescuing the pathological cardiac dysfunction induced by overexpression of PKC beta.