Regulation of Dipeptidyl Peptidase IV in the Post-stroke Rat Brain and In Vitro Ischemia: Implications for Chemokine-Mediated Neural Progenitor Cell Migration and Angiogenesis.
Regulation of Dipeptidyl Peptidase IV in the Post-stroke Rat Brain and In Vitro Ischemia: Implications for Chemokine-Mediated Neural Progenitor Cell Migration and Angiogenesis.
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DOI：
10.1007/s12035-016-0039-4
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发表时间：
2017-09
影响因子：
5.1
通讯作者：
Dempsey RJ
中科院分区：
文献类型：
--
作者：
Wesley UV;Hatcher JF;Ayvaci ER;Klemp A;Dempsey RJ
脑缺血引起脑微环境中蛋白酶的异常释放，时空影响血管神经发生。二肽基肽酶IV（DPPIV）是一种细胞表面分泌的蛋白酶，通过修饰主要趋化因子基质衍生因子SDF 1的功能来调节细胞粘附、迁移和血管生成，从而参与细胞外基质重塑。为了阐明DPPIV在缺血性脑中的可能关联，我们检测了DPPIV在中风后大鼠脑中的表达，以及通过氧葡萄糖剥夺（OGD）在体外缺血条件下的表达。我们进一步研究了DPPIV对SDF 1介导的体外趋化和血管生成功能的影响。DPPIV蛋白和mRNA水平在大鼠脑缺血皮质的修复阶段显著上调，特别是在神经元、星形胶质细胞和内皮细胞中。在体外暴露的神经元-2a神经元细胞和大鼠脑内皮细胞OGD导致DPPIV的上调。体外功能分析表明，DPPIV降低SDF 1介导的大鼠脑内皮细胞的血管生成潜能，并抑制Neuro-2a和神经前体细胞的迁移。蛋白质印迹分析显示磷酸化ERK 1/2和AKT的水平下降的DPPIV的存在下。DPPIV抑制剂恢复了SDF 1的作用。蛋白质组谱阵列筛选进一步揭示，DPPIV降低基质金属蛋白酶-9，一个关键的下游效应的ERK-AKT信号通路。总的来说，延迟诱导DPPIV响应缺血/再灌注表明，DPPIV可能在内源性脑组织重塑和修复过程中发挥重要作用。这可以通过调节SDF 1介导的细胞迁移和血管生成来介导。
Cerebral ischemia evokes abnormal release of proteases in the brain microenvironment that spatiotemporally impact angio-neurogenesis. Dipeptidyl peptidase IV (DPPIV), a cell surface and secreted protease has been implicated in extracellular matrix re-modeling by regulating cell adhesion, migration, and angiogenesis through modifying the functions of the major chemokine stromal derived factor, SDF1. To elucidate the possible association of DPPIV in ischemic brain, we examined the expression of DPPIV in the post-stroke rat brain, and under in vitro ischemia by oxygen glucose deprivation (OGD). We further investigated the effects of DPPIV on SDF1 mediated in vitro chemotactic and angiogenic functions. DPPIV protein and mRNA levels were significantly upregulated during repair phase in the ischemic cortex of the rat brain, specifically in neurons, astrocytes, and endothelial cells. In vitro exposure of Neuro-2a neuronal cells and rat brain endothelial cells to OGD resulted in up-regulation of DPPIV. In vitro functional analysis showed that DPPIV decreases the SDF1 mediated angiogenic potential of rat brain endothelial cells, and inhibits the migration of Neuro-2a and neural progenitor cells. Western blot analyses revealed decreased levels of phosphorylated ERK1/2 and AKT in presence of DPPIV. DPPIV inhibitor restored the effects of SDF1. Proteome profile array screening further revealed that DPPIV decreases matrix metalloproteinase-9, a key downstream effector of ERK-AKT signaling pathways. Overall, delayed induction of DPPIV in response to ischemia/reperfusion suggests that DPPIV may play an important role in endogenous brain tissue remodeling and repair processes. This may be mediated through modulation of SDF1 mediated cell migration, and angiogenesis.
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