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Role of Toll-like receptor in cardiovascular remodeling

Toll样受体在心血管重塑中的作用

基本信息

批准号：
17590702
负责人：
TAKEISHI Yasuchika
金额：
$ 2.24万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590702/
关键词：
hypertrophy remodeling heart failure cell signaling diacylglycerol kinase protein kinase C G protein myocardial infarction myocardinal infarction hypertophy

项目摘要

Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DAG) and controls cellular DAG levels, thus acting as a negative regulator of protein kinase C (PKC) and subsequent cellular signaling. We previously reported DGK inhibited angiotensin II and phenylephrine-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy. 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, Gq protein-coupled receptor signaling pathway including DAG and PKC are involved in this process. We examined whether DGK modifies LV remodeling after MI. Left anterior descending coronary artery was ligated in transgenic mice with cardiac-specific overexpression of DGKζ (DGKζ-TG) and wild-type (WT) mice. LV chamber dilatation, reduction of L … More V systolic function, and increases in LV weight and lung weight at 4 weeks after MI were attenuated in DGKζ-TG mice compared to WT mice. In the non-infarct area, fibrosis fraction and up-regulation of profibrotic genes such as transforming growth factor-β1, collagen type I, and collagen type III were blocked in DGKζ-TG mice. The survival rate at 4 weeks after MI was higher in DGKζ-TG mice than in WT mice.Thoracic transverse aortic constriction (TAC) was created in DGKζ-TG and WT mice. Increases in heart weight at 4 weeks after TAC were attenuated in DGKζ-TG mice compared to WT mice. Increases in inter-ventricular septal thickness, dilatation of the left ventricular cavity, and decreases in left ventricular systolic function were observed with echocardiography in WT mice at 4 weeks after TAC surgery. However, these structural and functional changes after TAC were attenuated in DGKζ-TG mice. In WT mice, cardiac fibrosis and up-regulation of profibrotic genes such as transforming growth factor-β1, collagen type I, and collagen type III were observed at 4 weeks after TAC. However cardiac fibrosis and gene induction of collagen type I and type III, but not transforming growth factor-βl, were blocked in DGKζ-TG mice.These results demonstrate the first evidence that DGKζ suppresses LV structural remodeling and fibrosis and improves survival after MI. DGKζ also prevents pressure overload-induced cardiac hypertrophy. DGKζ may be a potential novel therapeutic target to prevent cardiac hypertrophy and progression to heart failure. Less

二酰基甘油激酶（DGK）磷酸化二酰基甘油（DAG）并控制细胞DAG水平，因此充当蛋白激酶C（PKC）和随后的细胞信号传导的负调节剂。我们以前报道DGK抑制血管紧张素II和苯肾上腺素诱导的DAG-PKC信号通路的激活和随后的心脏肥大。左心室重构，包括心肌细胞坏死、瘢痕形成、左心室几何形状改变和心肌细胞肥大，是心肌梗死后心功能不全和死亡率的重要原因。虽然左室重构的确切细胞信号转导机制尚未完全阐明，但包括DAG和PKC在内的Gq蛋白偶联受体信号通路参与了这一过程。我们研究了DGK是否改变MI后的LV重构。左冠状动脉前降支结扎转基因小鼠与心脏特异性过表达的DGK-TG（DGK-TG）和野生型（WT）小鼠。左心室扩张，左心室缩小 ...更多信息与WT小鼠相比，MI后4周，DGK-TG小鼠的LV收缩功能以及LV重量和肺重量的增加减弱。在非梗死区，在DGK-TG小鼠中，纤维化分数和促纤维化基因如转化生长因子-β1、I型胶原和III型胶原的上调被阻断。心肌梗死后4周，DGK α-TG小鼠的存活率高于WT小鼠，DGK α-TG和WT小鼠均建立胸主动脉缩窄（TAC）模型。与WT小鼠相比，在TAC后4周，DGK-TG小鼠的心脏重量增加减弱。在TAC手术后4周，WT小鼠的超声心动图观察到室间隔厚度增加、左心室腔扩张和左心室收缩功能降低。然而，这些结构和功能的变化后，TAC在DGK-TG小鼠减弱。在WT小鼠中，TAC后4周观察到心脏纤维化和促纤维化基因（如转化生长因子-β1、I型胶原和III型胶原）的上调。然而，心肌纤维化和I型和III型胶原的基因诱导在DGK β 1-TG小鼠中被阻断，但转化生长因子β 1不被阻断。DGK β还可预防压力超负荷诱导的心脏肥大。DGKζ可能是预防心脏肥大和心力衰竭进展的潜在新治疗靶点。少

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adenovirus-mediated overexpression of diacylglycerol kinase ζ inhibits endothelia-1-induced cardiomyocyte hypertrophy.

腺病毒介导的二酰甘油激酶 z 的过度表达抑制内皮细胞 1 诱导的心肌细胞肥大。

DOI：
发表时间：
2005
期刊：
Circulation 111
影响因子：
0
作者：
Takahashi H;et al.
通讯作者：
et al.

Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic

p90 核糖体 S6 激酶介导的肾素原转化酶在缺血性和糖尿病中的作用

DOI：
发表时间：
2006
期刊：
myocardium. Circulation 113
影响因子：
0
作者：
Itoh S;Ding B;Shishido T;Lerner-Marmarosh N;Wang N;Maekawa N;Berk BC;Takeishi Y;Yan C;Blaxall BC;Abe J
通讯作者：
Abe J

Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury