Diacylglycerol kinase ζ attenuates pressure overload-induced cardiac hypertrophy
Diacylglycerol kinase ζ attenuates pressure overload-induced cardiac hypertrophy
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DOI：
10.1253/circj.71.276
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发表时间：
2007-02-01
影响因子：
3.3
通讯作者：
Kubota, Isao
中科院分区：
文献类型：
--
作者：
Harada, Mutsuo;Takeishi, Yasuchika;Kubota, Isao
背景 Gaq 蛋白偶联受体 (GPCR) 信号通路包括二酰基甘油 (DAG) 和蛋白激酶 C (PKC)，在心脏肥大和心力衰竭的发展中发挥着关键作用。 DAG 激酶 (DGK) 磷酸化 DAG 并控制细胞 DAG 水平，从而充当 GPCR 信号传导的调节器。先前有报道称，DGK 抑制 GPCR 激动剂诱导的 DAG-PKC 信号激活和随后的心肌细胞肥大，因此本研究的目的是检查 DGK 是否可以改变压力超负荷诱导的心脏肥大的发展。 方法和结果 在心脏特异性过表达 DGK zeta (DGK zeta-TG) 的转基因小鼠和野生型 (WT) 小鼠中产生胸主动脉横缩窄 (TAC)。与 WT 小鼠相比，DGK zeta-TG 小鼠在 TAC 后 4 周时心脏重量的增加有所减弱。 TAC术后4周超声心动图观察到WT小鼠室间隔厚度增加、左心室腔扩张和左心室收缩功能下降。然而，TAC 后的这些结构和功能变化在 DGK zeta-TG 小鼠中减弱。在 WT 小鼠中，TAC 后 4 周观察到心脏纤维化和原生基因的上调，例如转化生长因子-β1、I 型胶原和 III 型胶原。然而，在 DGK zeta-TG 小鼠中，心脏纤维化以及 I 型和 III 型胶原的基因诱导被阻断，但转化生长因子-β 1 并未被阻断。 结论 这些结果是 DGK 抑制心脏肥大和纤维化并防止压力超负荷引起的左心室收缩功能受损的第一个体内证据。
Background The Gaq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in the development of cardiac hypertrophy and heart failure. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. It has been previously reported that DGK inhibited GPCR agonist-induced activation of the DAG-PKC signaling and subsequent cardiomyocyte hypertrophy, so the purpose of this study was to examine whether DGK modifies the development of cardiac hypertrophy induced by pressure overload.Methods and Results Thoracic transverse aortic constriction (TAC) was created in transgenic mice with cardiac-specific overexpression of DGK zeta (DGK zeta-TG) and wild-type (WT) mice. Increases in heart weight at 4 weeks after TAC were attenuated in DGK zeta-TG mice compared with WT mice. Increases in interventricular septal thickness, dilatation of the left ventricular cavity, and decreases in left ventricular systolic function in WT mice were observed with echocardiography at 4 weeks after TAC surgery. However, these structural and functional changes after TAC were attenuated in DGK zeta-TG mice. In WT mice, cardiac fibrosis and up-regulation of protibrotic genes, such as transforming growth factor-beta 1, collagen type I, and collagen type III, were observed at 4 weeks after TAC. However, cardiac fibrosis and gene induction of type I and type III collagens, but not transforming growth factor-beta 1, were blocked in DGK zeta-TG mice.Conclusion These results are the first in vivo evidence that DGK suppresses cardiac hypertrophy and fibrosis and prevents impaired left ventricular systolic function caused by pressure overload.