Excess Salt Causes Cerebral Neuronal Apoptosis and Inflammation in Stroke-Prone Hypertensive Rats Through Angiotensin II-Induced NADPH Oxidase Activation
Excess Salt Causes Cerebral Neuronal Apoptosis and Inflammation in Stroke-Prone Hypertensive Rats Through Angiotensin II-Induced NADPH Oxidase Activation
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DOI：
10.1161/strokeaha.108.517284
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发表时间：
2008-11-01
期刊：
影响因子：
8.3
通讯作者：
Kim-Mitsuyama, Shokei
中科院分区：
文献类型：
--
作者：
Yamamoto, Eiichiro;Tamamaki, Nobuaki;Kim-Mitsuyama, Shokei
背景和目的--盐性脑损伤的确切机制尚不清楚。我们详细研究了血管紧张素II和NADPH氧化酶在易卒中自发性高血压大鼠(SHRSP)盐加速脑损伤中的作用。方法-我们检测了盐负荷对SHRSP脑内活性氧(ROS)、炎症和细胞凋亡的影响。盐负荷的SHRSP给予赋形剂、血管紧张素转换酶AT1受体阻滞剂valsartan或肼丙嗪，以比较它们对脑损伤的疗效。结果盐负荷后1周，SHRSP大鼠脑内NADPH氧化酶活性和ROS已明显升高，ED-1阳性细胞数和神经细胞凋亡率明显增加。因此，脑部NADPH氧化酶活性先于脑部炎症和神经细胞凋亡。尽管在盐负荷的SHRSP中，valsartan和肼的降压作用相似，valsartan对脑组织NADPH氧化酶活性的降低和ROS的降低要比肼强，valsartan对卒中的预防作用也比肼拉嗪更强。Valsartan但不能预防神经细胞的凋亡，这与valsartan抑制凋亡信号调节激酶1的激活有关。此外，与肼相比，valsartan更能预防脑部炎症，这与valsartan更多地抑制单核细胞趋化蛋白-1和肿瘤坏死因子-α的表达有关。因此，血管紧张素II直接参与了盐诱导的SHRSP神经元NADPH氧化酶的激活、ROS、细胞凋亡和炎症。Apoynin可减轻盐负荷SHRSP大鼠脑组织ROS、脑炎症、神经元凋亡和细胞凋亡信号调节蛋白1的激活，预防卒中，提示脑内NADPH氧化酶在盐诱导脑损伤中的作用。结论：血管紧张素II激活的NADPH氧化酶产生的ROS可导致SHRSP大鼠脑神经细胞的凋亡和炎症反应，从而导致卒中。(笔划。2008；39：3049-3056。)
Background and Purpose-The precise mechanism of salt-induced brain injury is unclear. We examined the detailed causative role of angiotensin II and NADPH oxidase in salt-accelerated brain injury of stroke-prone spontaneously hypertensive rats (SHRSP).Methods-We examined the effect of salt loading on brain reactive oxygen species (ROS), inflammation, and apoptosis in SHRSP. Salt-loaded SHRSP were given vehicle, valsartan (an angiotensin AT1 receptor blocker), or hydralazine to compare their efficacy on brain injury. We also examined the efficacy of apocynin (a NADPH oxidase inhibitor) on brain injury of salt-loaded SHRSP.Results-Cerebral NADPH oxidase activity and ROS in SHRSP were already increased at 1 week after salt loading followed by the significant increase in ED-1-positive cells and neuronal apoptosis. Thus, cerebral NADPH oxidase activation preceded cerebral inflammation and neuronal apoptosis. Despite comparable hypotensive effects between valsartan and hydralazine in salt-loaded SHRSP, valsartan reduced cerebral NADPH oxidase activity and ROS more than hydralazine being accompanied by more prevention of stroke by valsartan than hydralazine. Valsartan, but not hydralazine, prevented neuronal apoptosis, being associated with the suppression of apoptosis signal-regulating kinase 1 activation by valsartan. Moreover, cerebral inflammation was also prevented by valsartan more than hydralazine, being associated with more suppression of monocyte chemotactic protein-1 and tumor necrosis factor-alpha expressions by valsartan. Thus, angiotensin II was directly involved in salt-induced neuronal NADPH oxidase activation, ROS, apoptosis, and inflammation in SHRSP. Apocynin attenuated the enhancement of ROS, cerebral inflammation, neuronal apoptosis, and apoptosis signal-regulating kinase 1 activation and prevented stroke in salt-loaded SHRSP, indicating the causative role of cerebral NADPH oxidase in salt-induced brain injury.Conclusion-We obtained the evidence that excess salt, through ROS produced by angiotensin II-activated NADPH oxidase, caused cerebral neuronal apoptosis and inflammation as well as stroke in SHRSP. (Stroke. 2008; 39: 3049-3056.)