Experimental therapy with tissue kallikrein against cerebral ischemia
Experimental therapy with tissue kallikrein against cerebral ischemia
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DOI：
10.2741/1886
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发表时间：
2006-05-01
影响因子：
3.1
通讯作者：
Chao, L
中科院分区：
文献类型：
--
作者：
Chao, J;Chao, L
组织激肽释放酶是一种丝氨酸蛋白酶，能够裂解激肽原底物产生强有力的血管扩张剂激肽肽。激肽通过其受体信号传导介导一系列复杂的生理作用。腺病毒载体中的激肽释放酶基因的全身递送显著降低了高血压达尔盐敏感大鼠的中风诱导的死亡率、血压升高和主动脉肥大。使用大脑中动脉闭塞诱导的局灶性脑缺血大鼠模型，静脉内或脑室内激肽释放酶基因递送显著减少缺血/再灌注（I/R）诱导的神经功能缺损、脑梗死、神经元和胶质细胞凋亡以及炎性细胞浸润，同时促进缺血脑中的血管生成和神经发生。通过植入式微型泵连续输注亚降压剂量的组织激肽释放酶蛋白，可减少I/R诱导的神经功能障碍和脑梗死、炎症和氧化应激，而与激肽释放酶的降压作用无关。此外，即使在中风发作后一天递送，激肽释放酶也提供神经保护。激肽释放酶的保护作用被激肽B2受体拮抗剂艾替班特阻断。激肽B2受体缺陷小鼠死亡率和缺血后脑损伤的增加进一步证实了激肽B2受体在介导缺血性脑损伤保护作用中的作用。综上所述，这些结果表明激肽释放酶作为抗炎和抗氧化剂在保护脑免受缺血性卒中诱导的损伤中的新功能。这些发现也提高了组织激肽释放酶在急性缺血性中风治疗中可能具有价值的可能性。
Tissue kallikrein is a serine proteinase capable of cleaving kininogen substrate to produce the potent vasodilator kinin peptide. Kinin mediates a complex set of physiological actions through its receptor signaling. Systemic delivery of the kallikrein gene in an adenoviral vector significantly reduced stroke-induced mortality rate, blood pressure elevation, and aortic hypertrophy in hypertensive Dahl-salt sensitive rats fed a high salt diet. Using a focal cerebral ischemic rat model induced by middle cerebral artery occlusion, intravenous or intracerebroventricular kallikrein gene delivery significantly reduced ischemia/repefusion (I/R)-induced neurological deficits, cerebral infarction, neuronal and glial cell apoptosis, and inflammatory cell infiltration, while promoting angiogenesis and neurogenesis in the ischemic brain. A continuous infusion of a sub-depressor dose of tissue kallikrein protein through implanted minipump decreased I/R-induced neurological dysfunction and cerebral infarction, inflammation and oxidative stress independent of kallikrein's blood pressure-lowering effect. Moreover, kallikrein offered neuroprotection even when delivered at one day after the onset of stroke. Kallikrein's protective effects were blocked by the kinin B2 receptor antagonist icatibant. The role of the kinin B2 receptor in mediating the protective effect against ischemic brain injury was further confirmed by increases in mortality rate and post-ischemic brain injury in kinin B2 receptor-deficient mice. Taken together, these results suggest a novel function of kallikrein as an anti-inflammatory and anti-oxidative agent in protecting the brain against ischemic stroke-induced injuries. These findings also raise the possibility that tissue kallikrein may have value in the treatment of acute ischemic stroke.