Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke.
Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke.
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DOI：
10.1161/hypertensionaha.115.05185
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发表时间：
2015-07
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影响因子：
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通讯作者：
Sumners C
中科院分区：
文献类型：
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作者：
Bennion DM;Haltigan EA;Irwin AJ;Donnangelo LL;Regenhardt RW;Pioquinto DJ;Purich DL;Sumners C
血管紧张素转换酶2/血管紧张素-（1-7）/Mas轴代表诱导中风神经保护的有希望的靶点。在这里，探讨了中风引起的变化，内源性血管紧张素转换酶2和其他系统组件在Sprague道利大鼠的表达和活性。为了评估靶向该轴的治疗的临床可行性，并可能与中风引起的变化协同作用，我们还测试了脑卒中后全身给予血管紧张素转换酶2激活剂乙酰二氮烯的神经保护作用。在经历实验性内皮素-1诱导的缺血性中风的大鼠中，脑皮层和纹状体中的血管紧张素转换酶2活性在中风后24小时内增加。血清血管紧张素转换酶2活性在卒中后4小时内降低，但在卒中后3天反弹至高于基线水平。脑卒中后全身应用二氮烯治疗可减少梗死体积，改善神经功能，而脑血流量无明显增加。中央输注A-779（一种Mas受体拮抗剂）导致二甲双胍处理大鼠的梗死体积更大，单独中央输注血管紧张素转换酶2抑制剂MLN-4760使神经功能恶化。脑卒中后血管紧张素转换酶2保护通路的动态变化提示其可能是一个有利的治疗靶点。事实上，中风后血管紧张素转换酶2激活可能通过Mas信号以血流非依赖性方式产生显著的神经保护作用。我们的研究结果表明，靶向血管紧张素转换酶2/血管紧张素-（1-7）/Mas轴的卒中治疗药物可能与内源性卒中诱导的变化相互作用，为进一步研究其作为神经保护剂提供了希望。
The angiotensin converting enzyme 2/angiotensin-(1-7)/Mas axis represents a promising target for inducing stroke neuroprotection. Here, explored stroke-induced changes in expression and activity of endogenous angiotensin converting enzyme 2 and other system components in Sprague Dawley rats. To evaluate the clinical feasibility of treatments that target this axis and that may act in synergy with stroke-induced changes, we also tested the neuroprotective effects of diminazene aceturate, an angiotensin converting enzyme 2 activator, administered systemically post-stroke. Amongst rats that underwent experimental endothelin-1-induced ischemic stroke, angiotensin converting enzyme 2 activity in the cerebral cortex and striatum increased in the 24 hours after stroke. Serum angiotensin converting enzyme 2 activity was decreased within 4h post stroke, but rebounded to reach higher than baseline levels 3d post-stroke. Treatment following stroke with systemically-applied diminazene resulted in decreased infarct volume and improved neurological function without apparent increases in cerebral blood flow. Central infusion of A-779, a Mas receptor antagonist, resulted in larger infarct volumes in diminazene-treated rats, and central infusion of the angiotensin converting enzyme 2 inhibitor MLN-4760 alone worsened neurological function. The dynamic alterations of the protective angiotensin converting enzyme 2 pathway following stroke suggest that it may be a favorable therapeutic target. Indeed, significant neuroprotection resulted from post-stroke angiotensin converting enzyme 2 activation, likely via Mas signaling in a blood flow-independent manner. Our findings suggest that stroke therapeutics that target the angiotensin converting enzyme 2/angiotensin-(1-7)/Mas axis may interact cooperatively with endogenous stroke-induced changes, lending promise to their further study as neuroprotective agents.