Proteomic Protease Substrate Profiling of tPA Treatment in Acute Ischemic Stroke Patients: A Step Toward Individualizing Thrombolytic Therapy at the Bedside.
Proteomic Protease Substrate Profiling of tPA Treatment in Acute Ischemic Stroke Patients: A Step Toward Individualizing Thrombolytic Therapy at the Bedside.
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DOI：
10.1007/s12975-010-0047-z
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发表时间：
2010-12-01
影响因子：
6.9
通讯作者：
Lo EH
中科院分区：
文献类型：
--
作者：
Ning M;Sarracino DA;Buonanno FS;Krastins B;Chou S;McMullin D;Wang X;Lopez M;Lo EH
组织纤溶酶原激活剂 (tPA) 是 FDA 唯一批准的治疗急性缺血性中风的药物。但作为一种丝氨酸肽酶，静脉注射 tPA 可以影响其他可能与血脑屏障破坏有关的蛋白酶的表达。这种平行的细胞信号传导级联可能与颅内出血有关，这是 tPA 的主要副作用。在这里，我们描述了蛋白质组底物分析的初步尝试，即急性中风背景下人血浆的降解组学。使用串联质谱法和蛋白质阵列分析对静脉注射 tPA 之前和之后的急性中风患者血浆进行分析，以确定感兴趣的底物和蛋白酶。在未经 tPA 处理的中风血浆中，降解组学模式表明，中风发作后 3 小时内蛋白酶活性快速诱导，并在 24 小时内基本稳定。但在接受 tPA 治疗的患者中，来自同一患者的 tPA 治疗前和治疗后样本表现出不同的退化模式，甚至在中风发作后 3-5 天仍持续存在。随着时间的推移，匹配的没有中风的对照患者的退化组学特征几乎没有变化。我们的研究结果表明，tPA 治疗改变了急性中风患者的血浆降解组学特征。这些复合蛋白水解谱可以让我们了解 tPA 对床边细胞信号级联的多效性影响。这项研究支持在床边进行药物蛋白质组学的可行性，这可能最终使我们能够剖析中风溶栓相关治疗功效的机制。
Tissue plasminogen activator (tPA) is the only FDA-approved medical therapy for acute ischemic stroke. But as a serine peptidase, intravenous tPA can affect the expression of other proteases that may be implicated in blood–brain barrier breakdown. Such parallel cascades of cell signaling may be involved in intracranial hemorrhage, the major side effect of tPA. Here, we describe an initial attempt in proteomic substrate profiling, i.e., degradomics in human plasma within the context of acute stroke. Plasma from acute stroke patients were analyzed pre- and post-intravenous tPA using tandem mass spectrometry and protein array profiling to identify substrates and proteases of interest. In non-tPA-treated stroke plasma, degradomic patterns indicated a rapid induction of protease activity within 3 h of stroke onset that mostly stabilized by 24 h. But in tPA-treated patients, pre- and post-tPA samples from the same patient demonstrated distinct degradomic patterns that persisted even up to 3–5 days after stroke onset. Matching control patients without strokes had little change in degradomic profiles over time. Our findings demonstrate that tPA treatment changes the plasma degradomic profiles in acute stroke patients. These composite proteolytic profiles may provide a glimpse of the pleiotropic effects of tPA on cellular signaling cascades at the bedside. This study supports the feasibility of performing pharmaco-proteomics at the bedside, which may ultimately allow us to dissect mechanisms of thrombolysis-related therapeutic efficacy in stroke.
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DOI：
10.1016/j.jstrokecerebrovasdis.2009.06.001
发表时间：
2010-07
影响因子：
2.5
作者：
Hemmen, Thomas M.;Rapp, Karen S.;Emond, Jennifer A.;Raman, Rema;Lyden, Patrick D.
通讯作者：
Lyden, Patrick D.
影响因子：
120.7
作者：
Clark, WM;Wissman, S;Hamilton, S
通讯作者：
Hamilton, S
影响因子：
4.1
作者：
Abilleira, S;Montaner, J;Alvarez-Sabín, J
通讯作者：
Alvarez-Sabín, J
DOI：
10.1097/00004647-199611000-00036
发表时间：
1996-11-01
影响因子：
6.3
作者：
Hamann, GF;Okada, Y;delZoppo, GJ
通讯作者：
delZoppo, GJ
影响因子：
158.5
作者：
Hacke, Werner;Kaste, Markku;Toni, Danilo
通讯作者：
Toni, Danilo