Role of Toll-like receptor in cardiovascular remodeling

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，从而作为蛋白激酶C （PKC）和随后的细胞信号传导的负调节因子。我们之前报道过DGK抑制血管紧张素II和苯肾上腺素诱导的DAG-PKC信号激活和随后的心脏肥厚。左心室（LV）重构，包括心肌细胞坏死、瘢痕形成、左心室几何改变和心肌细胞肥大，是心肌梗死（MI）后心功能障碍和死亡率的重要因素。尽管左室重构的细胞信号传导机制尚未完全阐明，但Gq蛋白偶联受体信号通路包括DAG和PKC参与了这一过程。我们检测了DGK是否会改变心肌梗死后的左室重构。在心脏特异性过表达DGKζ (DGKζ- tg)的转基因小鼠和野生型（WT）小鼠中结扎左冠状动脉前降支。与WT小鼠相比，dgk - ζ- tg小鼠心肌梗死后4周左室扩张、左室收缩功能增强、左室重量和肺重量增加均减弱。在非梗死区，dgk - ζ- tg小鼠的纤维化分数和转化生长因子-β1、I型胶原和III型胶原等促纤维化基因的上调被阻断。dgk - ζ- tg小鼠心肌梗死后4周存活率高于WT小鼠。DGKζ-TG和WT小鼠均产生胸主动脉横缩（TAC）。与WT小鼠相比，在TAC后4周，dgk - ζ- tg小鼠的心脏重量增加减弱。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，左心室收缩功能下降。然而，在dgk - ζ- tg小鼠中，TAC后的这些结构和功能变化被减弱。TAC后4周，WT小鼠心肌纤维化，转化生长因子-β1、ⅰ型胶原、ⅲ型胶原等促纤维化基因上调。然而，dgk - ζ- tg小鼠的心脏纤维化和I型和III型胶原的基因诱导被阻断，而转化生长因子-β 1未被阻断。这些结果首次证明DGKζ抑制左室结构重塑和纤维化，并提高心肌梗死后的存活率。DGKζ还可以防止压力过载引起的心脏肥厚。DGKζ可能是一个潜在的新的治疗靶点，以防止心脏肥厚和进展为心力衰竭。少

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