uPA impairs cerebrovasodilation after hypoxia/ischemia through LRP and ERK MAPK.
uPA impairs cerebrovasodilation after hypoxia/ischemia through LRP and ERK MAPK.
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UPA通过LRP和ERK MAPK损害缺氧/缺血后的脑炎。
DOI：
10.1016/j.brainres.2008.06.115
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发表时间：
2008-09-22
期刊：
影响因子：
2.9
通讯作者：
Higazi, Abd Al-Roof
中科院分区：
文献类型：
--
作者：
Armstead, William M.;Cines, Douglas B.;Bdeir, Khalil;Kulikovskaya, Irina;Stein, Sherman C.;Higazi, Abd Al-Roof
我们以前观察到，可溶性尿激酶纤溶酶原激活物受体（suPAR）可防止新生猪缺氧/缺血（H/I）后高碳酸血症和低血压引起的血管舒张功能障碍。在这项研究中，我们研究了低密度脂蛋白相关蛋白（LRP）受体和ERK亚型的丝裂原活化蛋白激酶（MAPK）在uPA介导的损伤后H/I在小猪配备了一个封闭的颅窗血管舒张的作用。脑脊液uPA在H/I后1和4 h分别从9 ± 2增加到52 ± 8和140 ± 21 ng/ml。LRP拮抗剂受体相关蛋白（RAP）和抗LRP抗体在损伤后1h（17 ± 2 ng/ml）而非4 h可抑制CSF uPA的升高。免疫组化法检测到假手术组皮质uPA在H/I后4 h显著升高。在H/I后1和4 h检测到CSF ERK MAPK的磷酸化（活化），并被RAP阻断。H/I后4 h给予外源性uPA进一步刺激ERK MAPK磷酸化，RAP可阻断该作用。用RAP、抗LRP和suPAR对仔猪进行预处理可完全预防H/I后对低血压和高碳酸血症的反应受损，ERK MAPK拮抗剂U 0126可部分预防，但这些拮抗剂均不影响对异丙肾上腺素的反应。这些数据表明，在H/I后，uPA通过LRP依赖性过程上调，释放的uPA通过LRP和ERK MAPK依赖性途径损害高碳酸血症和扩张性扩张。这些数据表明，uPA上调和/或uPA介导的信号转导的调制可以保持缺氧/缺血后的血流动力学控制。
We have previously observed that soluble urokinase plasminogn activator receptor (suPAR) prevents impairment of cerebrovasodilation induced by hypercapnia and hypotension after hypoxia/ischemia (H/I) in the newborn pig. In this study, we investigated the role of low-density lipoprotein related protein (LRP) receptor and the ERK isoform of mitogen activated protein kinase (MAPK) in uPA-mediated impairment of vasodilation after H/I in piglets equipped with a closed cranial window. CSF uPA increased from 9 ± 2 to 52 ± 8 and 140 ± 21 ng/ml at 1 and 4h after H/I, respectively. The LRP antagonist receptor associated protein (RAP) and anti-LRP antibody blunted the increase in CSF uPA at 1h (17 ± 2 ng/ml) but not 4h post insult. uPA detectable in sham-treated cortex by immunhistochemistry was markedly elevated 4h after H/I. Phosphorylation (activation) of CSF ERK MAPK was detected at 1 and 4h post H/I and blocked by RAP. Exogenous uPA administered at 4h post H/I further stimulated ERK MAPK phosphorylation, which was blocked by RAP. Pre-treatment of piglets with RAP, anti-LRP, and suPAR completely prevented, and the ERK MAPK antagonist U 0126 partially prevented, impaired responses to hypotension and hypercapnia post H/I, but none of these antagonists affected the response to isoproterenol. These data indicate that uPA is upregulated after H/I through an LRP-dependent process and that the released uPA impairs hypercapnic and hypotensive dilation through an LRP- and ERK MAPK dependent pathway. These data suggest that modulation of uPA upregulation and/or uPA-mediated signal transduction may preserve cerebrohemodynamic control after hypoxia/ischemia.
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DOI：
10.1073/pnas.96.22.12866
发表时间：
1999-10-26
影响因子：
11.1
作者：
Alessandrini, A;Namura, S;Bonventre, JV
通讯作者：
Bonventre, JV
影响因子：
37.8
作者：
Benchenane, K;Berezowski, V;Vivien, D
通讯作者：
Vivien, D
DOI：
10.1073/pnas.89.16.7427
发表时间：
1992-08-15
影响因子：
11.1
作者：
BU, GJ;WILLIAMS, S;SCHWARTZ, AL
通讯作者：
SCHWARTZ, AL
影响因子：
8.3
作者：
Günther, G;Junker, R;Nowak-Göttl, U
通讯作者：
Nowak-Göttl, U
影响因子：
20.3
作者：
Higazi, AAR;Upson, RH;Cines, DB
通讯作者：
Cines, DB