Cardiac-specific overexpression of diacylglycerol kinase ζ attenuates left ventricular remodeling and improves survival after myocardial infarction
Cardiac-specific overexpression of diacylglycerol kinase ζ attenuates left ventricular remodeling and improves survival after myocardial infarction
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DOI：
10.1152/ajpheart.00927.2006
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发表时间：
2007-02-01
影响因子：
4.8
通讯作者：
Kubota, Isao
中科院分区：
文献类型：
--
作者：
Niizeki, Takeshi;Takeishi, Yasuchika;Kubota, Isao
心肌特异性过表达二酰甘油激酶xi减轻心肌梗死后左心室重构并提高存活率。美国生理学杂志心脏循环生理学292：H1105-H1112，2007年。首次发表于2006年10月27日; doi：10.1152/ajpheart.00927.2006。- 心肌梗死后左心室重构，包括心肌细胞坏死、瘢痕形成、左心室几何结构改变和心肌细胞肥大，是导致心功能不全和死亡的重要原因。虽然左室重构的确切细胞信号转导机制尚未完全阐明，但G（q）蛋白偶联受体信号通路，包括二酰基甘油（diacylglycerol，DAG）和PKC，参与了该过程。DAG激酶（DGK）磷酸化DAG并控制细胞DAG水平，因此充当PKC和随后的细胞信号传导的负调节剂。我们以前报道过DGK抑制血管紧张素II和苯肾上腺素诱导的DAG-PKC信号的激活和随后的心肌肥大。本研究的目的是检查DGK是否改变MI后的LV重构。在心脏特异性过表达DGK xi的转基因小鼠（DGK xi-TG）和野生型（WT）小鼠中结扎左前降支冠状动脉。左室腔扩张（4.12 +/-0.10 vs. 4.53 +/-0.32 mm，P <0.01），LV收缩功能下降（34.8 +/-8.3% vs. 28.3 +/-4.8%，P <0.01），左室重量增加与WT小鼠相比，在MI后4周，DGK xi-TG小鼠的肺重量（95 +/-3.6 vs. 111 +/-4.1 mg，P <0.05）和肺重量（160 +/-15 vs. 221 +/-25 mg，P <0.05）减轻。在非梗死区，DGK xi-TG小鼠的纤维化分数（0.51 +/-0.04，P <0.01）和促纤维化基因（如转化生长因子-β 1（P <0.01）、I型胶原（P <0.05）和III型胶原（P <0.01））的上调被阻断。心肌梗死后4wk存活率为61%，明显高于WT组的37%（P <0.01）。总之，这些结果证明了DGK xi抑制LV结构重塑和纤维化并改善MI后存活率的第一个证据。DGK xi可能是一个潜在的新的治疗靶点，以防止心肌梗死后左室重构。
Cardiac-specific overexpression of diacylglycerol kinase xi attenuates left ventricular remodeling and improves survival after myocardial infarction. Am J Physiol Heart Circ Physiol 292: H1105 - H1112, 2007. First published October 27, 2006; doi: 10.1152/ajpheart.00927.2006. - Left ventricular (LV) remodeling, including cardiomyocyte necrosis, scar formation, LV geometric changes, and cardiomyocyte hypertrophy, contributes to cardiac dysfunction and mortality after myocardial infarction (MI). Although precise cellular signaling mechanisms for LV remodeling are not fully elucidated, G(q) protein-coupled receptor signaling pathway, including diacylglycerol (DAG) and PKC, are involved in this process. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a negative regulator of PKC and subsequent cellular signaling. We previously reported that DGK inhibited angiotensin II and phenylephrine-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy. The purpose of this study was to examine whether DGK modifies LV remodeling after MI. Left anterior descending coronary artery was ligated in transgenic mice with cardiac-specific overexpression of DGK xi (DGK xi-TG) and wild-type (WT) mice. LV chamber dilatation (4.12 +/- 0.10 vs. 4.53 +/- 0.32 mm, P < 0.01), reduction of LV systolic function (34.8 +/- 8.3% vs. 28.3 +/- 4.8%, P < 0.01), and increases in LV weight (95 +/- 3.6 vs. 111 +/- 4.1 mg, P < 0.05) and lung weight (160 +/- 15 vs. 221 +/- 25 mg, P < 0.05) at 4 wk after MI were attenuated in DGK xi-TG mice compared with WT mice. In the noninfarct area, fibrosis fraction (0.51 +/- 0.04, P < 0.01) and upregulation of profibrotic genes, such as transforming growth factor-beta 1 ( P < 0.01), collagen type I (P < 0.05), and collagen type III (P < 0.01), were blocked in DGK xi-TG mice. The survival rate at 4 wk after MI was higher in DGK xi-TG mice than in WT mice (61% vs. 37%, P < 0.01). In conclusion, these results demonstrate the first evidence that DGK xi suppresses LV structural remodeling and fibrosis and improves survival after MI. DGK xi may be a potential novel therapeutic target to prevent LV remodeling after MI.