δPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo
δPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo
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DOI：
10.1016/j.brainres.2007.01.113
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发表时间：
2007-05-04
期刊：
影响因子：
2.9
通讯作者：
Mochly-Rosen, Daria
中科院分区：
文献类型：
--
作者：
Bright, Rachel;Steinberg, Gary K.;Mochly-Rosen, Daria
维持脑血管功能是减少急性缺血性事件（如中风）和慢性应激性疾病（如高血压）后损害的优先事项。缺血发作导致内皮细胞损伤、有害的炎症反应以及改变的神经元和星形胶质细胞对血管功能的调节。这些反过来又会导致脑血流受损和血脑屏障功能受损，促进微血管塌陷、水肿、出血性转化和神经恢复恶化。蛋白激酶C（PKC）是一种广泛表达的丝氨酸/苏氨酸激酶，参与调节动脉张力和微血管功能。然而，目前对单个PKC同工酶的作用还没有明确的认识。我们发现，腹膜内注射δ V1- 1-达特（47-57）（0.2 mg/kg，1 mL），一种δ PKC同工酶特异性肽抑制剂，可改善微血管病理学，与对照组动物相比，开放微血管数量增加92%，在正常血压大鼠大脑中动脉闭塞诱导的急性局灶性缺血后，脑血流量增加26%。此外，在高血压Dahl大鼠中急性递送Δ V1- 1-达特（47-57）增加脑血流量12%，并且持续递送Δ V1- 1-达特（47-57）（5 μ L/h，1 mM），在MCA闭塞90分钟诱导的急性卒中后，梗死面积减少25%。这些发现表明δ PKC是在急性和慢性脑血管应激条件下保护微血管结构和功能的重要治疗靶点。(c)2007 Elsevier B. V.保留所有权利。
Maintaining cerebrovascular function is a priority for reducing damage following acute ischemic events such as stroke, and under chronic stress in diseases such as hypertension. Ischemic episodes lead to endothelial cell damage, deleterious inflammatory responses, and altered neuronal and astrocyte regulation of vascular function. These, in turn, can lead to impaired cerebral blood flow and compromised blood-brain barrier function, promoting microvascular collapse, edema, hemorrhagic transformation, and worsened neurological recovery. Multiple studies demonstrate that protein kinase C (PKC), a widely expressed serine/threonine kinase, is involved in mediating arterial tone and microvascular function. However, there is no clear understanding about the role of individual PKC isozymes. We show that intraperitoneal injection of delta V1- 1-TAT(47-57) (0.2 mg/kg in 1 mL), an isozyme-specific peptide inhibitor of delta PKC improved microvascular pathology, increased the number of patent microvessels by 92% compared to control-treated animals, and increased cerebral blood flow by 26% following acute focal ischemia induced by middle cerebral artery occlusion in normotensive rats. In addition, acute delivery of delta V1- 1-TAT(47-57) in hypertensive Dahl rats increased cerebral blood flow by 12%, and sustained delivery delta V1- 1-TAT(47-57) (5 uL/h, 1 mM), reduced infarct size by 25% following an acute stroke induced by MCA occlusion for 90 min. Together, these findings demonstrate that delta PKC is an important therapeutic target for protection of microvascular structure and function under both acute and chronic conditions of cerebrovascular stress. (c) 2007 Elsevier B.V. All rights reserved.