Physiological significance of big mitogen-activated protein kinase 1 in metabolic syndrome

本课题通过糖尿病大鼠模型动物和培养细胞，探讨大丝裂原活化蛋白激酶1在代谢综合征中的生理意义。1)在2型糖尿病大鼠OLETF模型中，BMK1在小动脉血管平滑肌中被激活。在袖带损伤的股动脉外膜部位的动脉粥样硬化模型小鼠中也得到了类似的结果。这些发现提示BMK1的激活参与了糖尿病微血管病变的发病机制。2)在培养的大鼠主动脉平滑肌细胞（RASMC）实验中，血小板衍生生长因子（PDGF）以时间和浓度依赖的方式刺激BMK1的激活。SHP-2和Gab1存在于BMK1的上游，被PDGF刺激激活。PDGF还能刺激RASMC迁移，而转染MEK5则能抑制RASMC迁移。这些发现提示BMK1参与炎症性血管重构的发病机制。3)在人脐静脉内皮细胞（HUVEC）实验中，层流剪切应力刺激BMK1的激活。TNF-α刺激c-Jun n -末端激酶（INK）的激活，而这种激活被层流抑制。BMK1在内皮细胞中的生理意义也得到了证实。从这些体内和体外研究结果来看，BMK1可能参与代谢综合征的血管损伤，BMK1可能是治疗代谢综合征的药物靶点之一。

In the current research project, we investigated the physiological significance of big mitogen-activated protein kinase 1 in metabolic syndrome using the model animals of diabetic rats and cultured cells.1) In the type 2 diabetic rat model OLETF, BMK1 was activated in vascular smooth muscles of small arteries. Similar results were obtained in the atherosclerotic model mice at the site of adventitia of cuff-injured femoral artery. From these findings, it was suggested that BMK1 activation is involved in the pathogenesis of diabetic microangiopathy.2) In experiments using cultured rat aortic smooth muscle cells (RASMC), platelet-derived growth factor (PDGF) stimulated BMK1 activation in a time and concentration-dependent manner. SHP-2 and Gab1 exist upstream of BMK1 and were activated by PDGF stimulation. PDGF also stimulated RASMC migration, which was inhibited by a transfection with dominant-negative MEK5. These findings suggest that BMK1 is involved in the pathogenesis of inflammatory vascular remodeling.3) In experiments using human umbilical vein endothelial cells (HUVEC), laminar fluid shear stress stimulated BMK1 activation. TNF-α stimulates c-Jun N-terminal kinase (INK) activation, which was inhibited by laminar flow. Physiological significance of BMK1 in endothelial cells has also confirmed. From these in vivo and in vitro findings, BMK1 is suggested to be involved in vascular injury in metabolic syndrome and BMK1 may be one of the drug targets for treatment of metabolic syndrome.