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首页> 外文期刊>Translational Stroke Research >RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis
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RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis

机译：RBC偶联的tPA可以防止tPA加重JNK MAPK介导的脑光血栓形成后，ATP和Ca敏感性K通道介导的脑血管舒张损害。

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The sole Food and Drug Administration-approved treatment for acute stroke is tissue-type plasminogen activator (tPA), but tPA aggravates impairment of cerebrovasodilation during hypotension in a newborn pig photothrombotic model of stroke. Coupling to carrier red blood cells (RBC) enhances thrombolytic effects of tPA, while reducing its side effects. ATP- and Ca-sensitive K channels (Katp and Kca) are important regulators of cerebrovascular tone and mediate cerebrovasodilation during hypotension. Mitogen-activated protein kinase, a family of at least three kinases, ERK, p38, and c-Jun-N-terminal kinase (JNK), is upregulated after photothrombosis. This study examined the effect of photothrombosis on Katp- and Kca-induced cerebrovasodilation and the roles of tPA and JNK during/after injury. Photothrombosis blunted vasodilation induced by the Katp agonists cromakalim, calcitonin gene-related peptide, and the Kca agonist NS 1619, which was aggravated by injection of tPA. In contrast, both pre- or post-injury thrombosis injection of RBC-tPA and JNK antagonist SP 600125 prevented impairment of Katp- and Kca-induced vasodilation. Therefore, JNK activation in thrombosis impairs K channel-mediated cerebrovasodilation. Standard thrombolytic therapy of central nervous system ischemic disorders using free tPA poses the danger of further dysregulation of cerebrohemodynamics by impairing cation-mediated control of cerebrovascular tone, whereas RBC-coupled tPA both restores reperfusion and normalizes cerebral hemodynamics.
机译：食品和药物管理局批准的急性中风的唯一治疗方法是组织型纤溶酶原激活物（tPA），但在新生猪的光血栓性中风模型中，tPA加重了低血压期间脑血管舒张功能的损害。与载体红细胞（RBC）偶联可增强tPA的溶栓作用，同时减少其副作用。 ATP和Ca敏感的K通道（Katp和Kca）是低血压期间脑血管紧张的重要调节剂，并介导脑血管舒张。在血栓形成后，丝裂素激活的蛋白激酶（至少三个激酶，ERK，p38和c-Jun-N-末端激酶（JNK）的家族）被上调。这项研究检查了光血栓形成对Katp和Kca诱导的脑血管舒张的影响以及tPA和JNK在损伤期间/之后的作用。 Katp激动剂cromakalim，降钙素基因相关肽和Kca激动剂NS 1619诱导的光血栓形成使血管舒张减弱，而tPA注射会加剧这种情况。相反，损伤前或损伤后的RBC-tPA和JNK拮抗剂SP 600125的血栓注射均预防了Katp和Kca诱导的血管舒张功能受损。因此，血栓形成中的JNK激活削弱了K通道介导的脑血管舒张功能。使用游离tPA的中枢神经系统缺血性疾病的标准溶栓治疗会通过损害阳离子介导的脑血管紧张度控制而进一步导致脑血流动力学失调，而RBC偶联的tPA既能恢复再灌注，又能使脑血流动力学正常化。

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