Role of AKT-glycogen synthase kinase axis in monocyte activation in human beings with and without type 2 diabetes.
Role of AKT-glycogen synthase kinase axis in monocyte activation in human beings with and without type 2 diabetes.
复制标题
DOI：
10.1111/j.1582-4934.2009.00900.x
复制
发表时间：
2010-06
影响因子：
5.3
通讯作者：
Basu A
中科院分区：
文献类型：
--
作者：
Nandy D;Asmann YW;Mukhopadhyay D;Basu A
单核细胞被趋化因子激活是动脉粥样硬化过程开始的重要触发因素。血小板活化因子（PAF）是一种公认的趋化因子，其循环水平在2型糖尿病中升高，与加速动脉粥样硬化有关。为了探索分子基础，我们研究了PAF诱导单核细胞活化的信号通路。PAF增加从THP-1细胞，非糖尿病和糖尿病受试者获得的单核细胞的迁移。这种作用被AKT抑制所阻断。它是通过糖原合成酶激酶（GSK）-3的NS 9的磷酸化来实现的，这被AKT抑制剂完全阻断。此外，PAF诱导的GSK-3β磷酸化与Rac-1激活和Rho-A失活相关，导致迁移。特异性地，抑制GSK-3β磷酸化也通过磷酸化AKT和激活Rho-A增强THP-1、ND和糖尿病单核细胞中的单核细胞迁移，这与GSK无关。当（i）Rho-A显性失活突变体的过表达逆转GSK抑制剂诱导的单核细胞迁移和（ii）AKT抑制阻断GSK抑制剂诱导的Rho-A活性时，这得到了验证。组成型活性ARAP 3（Rho-GAP）似乎在GSK抑制期间对单核细胞活性具有调节作用。最后，与无糖尿病的人相比，抑制单核细胞GSK-3β活性（通过抑制剂和遗传操作）导致糖尿病患者的迁移增强。我们得出结论，糖尿病单核细胞对GSK-3β抑制的迁移能力增加。因此，开发用于治疗糖尿病代谢并发症的GSK抑制剂应谨慎使用。
Monocyte activation by chemokines is a vital trigger for initiation of atherosclerotic process. Circulating levels of platelet activating factor (PAF), a recognized chemokine, is known to be increased in type 2 diabetes that is linked to accelerated atherosclerosis. To explore the molecular basis we examined the signalling pathways involved in PAF induced monocyte activation. PAF increased migration in monocytes obtained from THP-1 cells, nondiabetic and diabetic subjects. This effect was blocked by AKT inhibition. It did so by phosphorylation of glycogen synthase kinase (GSK)-3βS9, which was completely blocked by AKT inhibition. Additionally, PAF induced GSK-3β phosphorylation was linked to Rac-1 activation and Rho-A inactivation leading to migration. Paradoxically, inhibition of GSK-3β phosphorylation also augmented monocyte migration in THP-1, ND and diabetic monocytes through phosphorylation of AKT and activation of Rho-A that was independent of GSK. This was validated when (i) overexpression of dominant negative mutants of Rho-A reversed GSK inhibitor induced monocyte migration and (ii) AKT inhibition blocked GSK inhibitor induced Rho-A activity. Constitutively active ARAP3 (Rho-GAP) appears to have a regulatory role in monocyte activity during GSK inhibition. Finally, inhibition of monocyte GSK-3β activity (by inhibitors and genetic manipulation) led to enhanced migration in diabetes compared to persons without diabetes. We conclude that diabetic monocytes show increased migratory capacity in response to GSK-3β inhibition. GSK inhibitors developed to treat the metabolic complications of diabetes should therefore be used with caution.
登录
查看更多内容
影响因子：
9.2
作者：
Higuchi, M;Masuyama, N;Gotoh, Y
通讯作者：
Gotoh, Y
影响因子：
2.6
作者：
Ratta, M;Curti, A;Lemoli, RM
通讯作者：
Lemoli, RM
影响因子：
120.1
作者：
Cohen, P;Goedert, M
通讯作者：
Goedert, M
影响因子：
56.9
作者：
Randolph, GJ;Beaulieu, S;Muller, WA
通讯作者：
Muller, WA
影响因子：
16
作者：
Krugmann, S;Anderson, KE;Hawkins, PT
通讯作者：
Hawkins, PT