Roles of signal transduction systems mediated by diacylglyoerol in cardiac hypertrophy and failure

由几种神经体液因子如血管紧张素II和内皮素-1触发的信号传导之后是磷脂酶C的活化，其导致脂质第二信使1，2-二酰基甘油的产生。1，2-二酰甘油是磷脂依赖性蛋白激酶C（PKC）的激活剂，在心肌缺血预处理中可引起心肌肥大和心肌保护等细胞反应。因此，1，2-二酰基甘油信号必须严格调节以获得适当的反应。二酰基甘油激酶（DGK）是一种负责通过将1，2-二酰基甘油转化为磷脂酸（PA）来控制1，2-二酰基甘油细胞水平的酶，从而作为PKC的调节剂。为了检测二酰基甘油激酶（DGK）和磷脂酸磷酸酶（PAP）在压力超负荷心脏肥大中的参与，对大鼠进行升主动脉缩窄3，7，假手术组28天。与假手术大鼠相比，结扎大鼠左心室（LV）重量进行性增加。术后28 d，结扎组大鼠左室心肌DGKε mRNA表达较假手术组明显降低，而DGK ε mRNA和PAP 2b mRNA表达无明显变化。心肌梗死大鼠左室心肌中的DGK β蛋白从颗粒移位到胞浆。此外，与假手术组相比，结扎组大鼠左室心肌1，2-二酰甘油含量和颗粒部分PKCδ蛋白表达显著增加。提示DGKε和DGK β在压力超负荷性心肌肥厚的发生发展中起着不同的作用，且两种同工酶的调节存在差异。

The signaling triggered by several neurohumoral factors such as angiotensin II and endothelin-1 is followed by the activation of phospholipase C which results in the production of a lipid second messenger, 1,2-diacylglycerol. 1,2-diacylglycerol serves as an activator of phospholipid-dependent protein kinase C (PKC), which elicits several cellular responses in the heart, including cardiac hypertrophy and protection of cardiomyocytes in ischemic preconditioning. Therefore, 1,2 diacyoglycerol signaling must be strictly regulated for the appropriate response. diacylglycerol kinase (DGK) is an enzyme that is responsible for controlling the 1,2-diacylglycerol cellular level by converting it to phosphatidic acid (PA), thus acting as a regulator of PKC.To examine the involvement of diacylglycerol kinase (DGK) and phosphatidic acid phosphatase (PAP) in pressure overloaded cardiac hypertrophy, rats were subjected to either ascending aortic banding for 3, 7, and 28 days or sham operation. In comparison with sham-operated rats, the left ventricular (LV) weight of the aortic-banded rats increased progressively. At 28 days after surgery, the expression of DGKε mRNA but not DGKζ or PAP2b mRNA in the LV myocardium significantly decreased in the aortic-banded rats compared with the sham-operated rats. DGKζ protein in the LV myocardium translocated from the particulate to the cytosolic compartment in the aortic-banded rats. Furthermore, the myocardial content of 1,2-diacylglycerol and PKCδ protein expression in the particulate fraction of the LV myocardium significantly increased in aortic-banded rats compared with sham-operated rats. These results suggest that DGKε and DGKζ play distinct roles in the development of pressure overloaded cardiac hypertrophy and that the two isozymes are differentially regulated.