Diacylglycerol kinase ζ rescues gaq-induced heart failure in transgenic mice
Diacylglycerol kinase ζ rescues gaq-induced heart failure in transgenic mice
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DOI：
10.1253/circj.72.309
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发表时间：
2008-02-01
影响因子：
3.3
通讯作者：
Kubota, Isao
中科院分区：
文献类型：
--
作者：
Niizeki, Takeshi;Takeishi, Yasuchika;Kubota, Isao
背景G α q蛋白偶联受体（GPCR）信号通路包括甘油二酯（DAG）和蛋白激酶C（PKC），在心肌肥厚和心力衰竭（HF）的发生发展中起重要作用。据报道，G蛋白α q亚基的组成型活性突变体（G α q-TG）在转基因小鼠心脏中的表达诱导心脏肥大，并且致死性HE DAG激酶（DGK）催化DAG并控制其细胞水平，从而充当GPCR信号传导的调节剂。已经发现心脏特异性过表达DGK zeta的转基因小鼠，（DGK zeta-TG）抑制GPCR激动剂诱导的激活或DAG-PKC信号传导和随后的心脏肥大，因此，本研究验证了DGK zeta可以拯救G α q-TG小鼠免于发生HE的假设。方法和结果通过将G α q-TG与DGKzeta-TG小鼠杂交，产生具有DGKzeta和G α q两者的心脏特异性过表达的（G α q/DGKzeta-TG），并分析病理生理后果。DGK zeta可预防心功能不全，这是通过G alpha q-TG小鼠左心室（LV）尺寸扩张、LV缩短分数降低和LV舒张末期压显著升高来确定的。PKC亚型的易位，c-jun N-末端激酶和p38丝裂原活化蛋白激酶在G α q-TG小鼠中的磷酸化活性被DGKzeta减弱。DGK zeta提高了G α q-TG mice. Conclusions的存活率，这些结果表明，第一个证据表明，DGK zeta块心功能不全，并通过激活G α q蛋白在体内心脏中没有检测到的不良反应，并表明DGK zeta是一个新的治疗靶点HF的致命HF。
Background The G alpha q 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 (HF). It has been reported that the expression of a constitutively active mutant of the G protein alpha q subunit in the hearts of transgenic mice (G alpha q-TG) induces cardiac hypertrophy and lethal HE DAG kinase (DGK) catalyzes DAG and controls its cellular levels, thus acting as a regulator of GPCR signaling. It has been found that transgenic mice with cardiac-specific overexpression of DGK zeta (DGK zeta-TG) inhibit GPCR agonist-induced activation or the DAG-PKC signaling and subsequent cardiac hypertrophy, so this study tested the hypothesis that DGK zeta could rescue G alpha q-TG mice from developing HEMethods and Results Double transgenic mice (G alpha q/DGK zeta-TG) with cardiac-specific overexpression of both DGK zeta and G alpha q were generated by crossing G alpha q-TG with DGK zeta-TG mice, and the pathophysiological consequences were analyzed. DGK zeta prevented cardiac dysfunction, determined by dilatation of left ventricular (LV) dimensions, reduction of LV fractional shortening, and marked increases in LV end-diastolic pressure in G alpha q-TG mice. Translocation of PKC isoforms, phosphorylation activity of c-jun N-terminal kinase and p38 mitogen-activated protein kinase in G alpha q-TG mice were attenuated by DGK zeta. DGK zeta improved the survival rate of G alpha q-TG mice.Conclusions These results demonstrate the first evidence that DGK zeta blocks cardiac dysfunction and progression to lethal HF by activated G alpha q protein without detectable adverse effects in the in-vivo heart and suggest that DGK zeta is a novel therapeutic target for HF.