Cardiopulmonary bypass reduces peripheral microvascular contractile function by inhibition of mitogen-activated protein kinase activity
Cardiopulmonary bypass reduces peripheral microvascular contractile function by inhibition of mitogen-activated protein kinase activity
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DOI：
10.1067/msy.2003.229
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发表时间：
2003-08-01
期刊：
影响因子：
3.8
通讯作者：
Sellke, FW
中科院分区：
文献类型：
--
作者：
Khan, TA;Bianchi, C;Sellke, FW
背景。有丝分裂原活化蛋白激酶（MAPK）参与了体外循环（CPB）的病理生理反应。MAPK被磷酸酶如MAPK磷酸酶-1 （MKP-1）失活。我们假设MAPK介导CPB引起的人类周围微血管收缩功能障碍。CPB前后分别取骨骼肌。检测MKP-1、活化的细胞外信号调节激酶1/2 （ERK1/2）和p38蛋白水平。检测MKP-1基因表达。用视频显微镜观察外周微血管对血管加压药物的反应。用PD98059 （ERK1/2）和SB203580 （p38）抑制MAPK后，还测量了收缩功能。ERK1/2、p38和MKP-1通过免疫组化和原位杂交进行定位。CPB后外周组织ERK1/2和p38活性降低。CPB后mkp - 1升高。CPB后外周小动脉对苯肾上腺素和加压素的收缩反应减弱。PD98059和SB203580处理后微血管反应性也有所降低。组织切片显示ERK1/2、p38和MKP-1定位于外周小动脉。外周小动脉对苯肾上腺素和抗利尿素的收缩反应依赖于ERK1/2和p38， CPB后收缩反应减弱。这些结果表明，人类CPB后，MAPK通路的改变在一定程度上调节了周围微血管功能障碍。
Background. Mitogen-activated protein kinases (MAPK) have been implicated in pathophysiologic responses to cardiopulmonary bypass (CPB). MAPK are deactivated by phosphatases, such as MAPK phosphatase-1 (MKP-1). We hypothesized that MAPK mediate peripheral microvascular contractile dysfunction caused by CPB in humans.Methods. Skeletal muscle was harvested before and after CPB. Protein levels of MKP-1 and activated extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 were measured. MKP-1 gene expression was measured. Peripheral microvessel responses to vasopressors were studied by videomicroscopy. Contractile function also was measured after MAPK inhibition with PD98059 (ERK1/2) and SB203580 (p38). ERK1/2, p38, and MKP-1 were localized by immunohistochemistry and in situ hybridization.Results. ERK1/2 and p38 activity was decreased in peripheral tissue after CPB. MKP-l was increased after CPB. Contractile responses of Peripheral arterioles to phenylephrine and vasopressin were decreased after CPB. Microvessel reactivity also was reduced after treatment with PD98059 and SB203580. ERK1/2, p38, and MKP-1 localized to peripheral arterioles in tissue sections.Conclusion. CPB reduces ERK1/2 and p38 activity in peripheral tissue, potentially by MKP-1 Contractile responses of peripheral arterioles to phenylephrine and vasopressin are dependent on ERK1/2 and p38 and are decreased after CPB. These results suggest that alterations in MAPK pathways in part regulate peripheral microvascular dysfunction after CPB in humans.