Characterization of lymphocyte β2-adrenoceptor signalling in patients with left ventricular volume overload disease
Characterization of lymphocyte β2-adrenoceptor signalling in patients with left ventricular volume overload disease
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DOI：
10.1046/j.1440-1681.2002.03625.x
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发表时间：
2002-03-01
影响因子：
2.9
通讯作者：
Al-Halees, Z
中科院分区：
文献类型：
--
作者：
Dzimiri, N;Basco, C;Al-Halees, Z
1.使用动物实验模型的研究表明，β（2）-肾上腺素受体解偶联与心力衰竭中G蛋白偶联受体激酶（GRK）2/3表达的改变有关。然而，这一途径的组分在人类疾病中的功能表达尚未完全阐明。在本研究中，我们评估了左心室容量超负荷（VOL）患者β 2-肾上腺素受体信号成分的调节取决于超负荷严重程度的可能性。检测VOL患者淋巴细胞GRK 2-6、β-arrestins 1和2、β（2）-肾上腺素能受体mRNA和蛋白水平的表达，以及腺苷酸环化酶、蛋白激酶（PK）A和PKC的活性，并以健康献血员为对照.在患者组中，GRK 2 mRNA增加61%（P < 0.001），GRK 3增加54%（P < 0.005），GRK 5增加5倍（P < 0.001），β-arrestin 2 mRNA增加40%（P < 0.05）。这些增加与GRK 2增加6倍、GRK 3增加2倍和GRK 5蛋白水平增加1.3倍相抵消。这些变化与β（2）-肾上腺素受体mRNA的显著降低、腺苷酸环化酶的基础、催化和受体介导活性以及毛喉素刺激活性对鸟苷酰亚胺二磷酸增强抑制的敏感性相关。一般来说，GRK 2和GRK 5 mRNA的增加与血流动力学负荷的严重性呈正相关，这是通过左心室缩短分数的变化来确定的.结果表明，VOL诱导淋巴细胞β 2-肾上腺素受体特异性GRK和β-arrestin 2表达的增加与β 2-肾上腺素受体水平的衰减有关。可以推测，心脏循环系统部分通过改变β（2）-肾上腺素受体信号传导来适应改变的血液动力学功能需求。
1. Studies using animal experimental models have suggested that the beta(2)-adrenoceptor is uncoupled in association with alterations in the expression of G-protein-coupled receptor kinases (GRK) 2/3 in heart failure. However, the functional expression of the components of this pathway in human disease has not been fully elucidated yet. In the present study, we evaluated the possibility that the regulation of beta(2)-adrenoceptor signalling components in patients with left ventricular volume overload (VOL) depends on the severity of the overload.2. We characterized the lymphocyte GRK 2-6, beta-arrestins 1 and 2, beta(2)-adrenoceptor expression at the mRNA and protein levels, as well as the activity of adenylyl cyclase, protein kinases (PK) A and PKC in patients with VOL using healthy blood donors as controls.3. In the patient group, GRK2 mRNA was increased by 61% (P < 0.001), GRK3 was increased by 54% (P < 0.005), GRK5 was increased fivefold (P < 0.001) and the beta-arrestin 2 mRNA was increased by 40% (P < 0.05). These increases were paralleled with a sixfold increase in GRK2, a twofold increase in GRK3 and a 1.3-fold increase in GRK5 protein levels. These changes were associated with a significant decrease in beta(2)-adrenoceptor mRNA, the basal, catalytic and receptor-mediated activity of adenylyl cyclase and sensitization of the forskolin-stimulated activity towards augmented inhibition by guanylimidodiphosphate. In general, the increase in GRK2 and 5 mRNA exhibited a positive correlation with the gravity of the haemodynamic load, as determined by changes in left ventricular fractional shortening.4. The results suggest that VOL induces an increase in the expression of lymphocyte beta(2)-adrenoceptor-specific GRK and beta-arrestin 2 in association with an attenuation in beta(2)-adrenoceptor levels. It can be speculated that the cardiac circulatory system adapts itself to altered haemodynamic functional demands partly by altering beta(2)-adrenoceptor signalling.