PAI-1-derived peptide EEIIMD prevents hypoxia/ischemia-induced aggravation of endothelin- and thromboxane-induced cerebrovasoconstriction.
PAI-1-derived peptide EEIIMD prevents hypoxia/ischemia-induced aggravation of endothelin- and thromboxane-induced cerebrovasoconstriction.
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DOI：
10.1007/s12028-013-9906-2
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发表时间：
2014-02
影响因子：
3.5
通讯作者：
Higazi AA
中科院分区：
文献类型：
--
作者：
Armstead WM;Riley J;Cines DB;Higazi AA
由于中风、分娩问题或分娩后呼吸管理，围产儿期间婴儿经常暴露于脑缺氧和脑缺血（H/I）。FDA批准的唯一治疗急性中风的药物是组织型纤溶酶原激活剂（tPA）。内源性tPA在猪H/I后低血压的反应中上调并增强了心动脉扩张的损害。丝裂原活化蛋白激酶（MAPK）是一个至少有3种激酶的家族，ERK、p38和JNK在H/I后也上调，ERK有助于血管舒张受损。本研究探讨了H/I加重血管对CNS缺血时释放的两种重要促收缩介质内皮素-1 （ET-1）和凝血素的反应，而tPA和ERK MAPK进一步增强了这一反应。封闭颅窗、氯氯蔗糖麻醉的仔猪出现脑缺氧（通过吸入N2， pO2 35 mmHg，持续10分钟），紧接着出现缺血（颅内压升高20分钟）。H/I加重了ET-1和血栓素模拟物u46619引起的头动脉血管收缩。增强的血管收缩反应被EEIIMD （tPA信号和血管活性的抑制剂）阻断，但其无活性类似物EEIIMR没有改变。ELISA检测脑脊液ERK MAPK浓度H/I升高，tPA增强，EEIIMD阻断。ERK MAPK拮抗剂u0126阻断H/I增强ET-1和u46619血管收缩。这些数据表明，H/I通过上调内源性tPA和ERK MAPK，加重ET-1和血栓素介导的脑血管收缩。
Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery or post delivery respiratory management. The sole FDA approved treatment for acute stroke is tissue-type plasminogen activator (tPA). Endogenous tPA is upregulated and potentiates impairment of pial artery dilation in response to hypotension after H/I in pigs. Mitogen-activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after H/I, with ERK contributing to impaired vasodilation. This study examined the hypothesis that H/I aggravates the vascular response to two important procontractile mediators released during CNS ischemia, endothelin-1 (ET-1) and thromboxane, which is further enhanced by tPA and ERK MAPK. Cerebral hypoxia (pO2 35 mmHg for 10 min via inhalation of N2) followed immediately by ischemia (global intracranial pressure elevation for 20 min) was produced in chloralose anesthetized piglets equipped with a closed cranial window. H/I aggravated pial artery vasconstriction induced by ET-1 and the thromboxane mimetic U 46619. Potentiated vasoconstrictor responses were blocked by EEIIMD, an inhibitor of tPA’s signaling and vascular activities, but unchanged by its inactive analogue EEIIMR. The cerebrospinal fluid concentration of ERK MAPK determined by ELISA was increased by H/I, potentiated by tPA, but blocked by EEIIMD. The ERK MAPK antagonist U 0126 blocked H/I augmented enhancement of ET-1 and U 46619 vasoconstriction. These data indicate that H/I aggravates ET-1 and thromboxane mediated cerebral vasoconstriction by upregulating endogenous tPA and ERK MAPK.