Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats
Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats
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DOI：
10.1161/hypertensionaha.111.00469
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发表时间：
2013-06-01
期刊：
影响因子：
8.3
通讯作者：
Chan, Julie Y. H.
中科院分区：
文献类型：
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作者：
Chao, Yung-Mei;Lai, Ming-Derg;Chan, Julie Y. H.
内质网（ER）正常功能的紊乱导致细胞中错误折叠或未折叠蛋白质的积累，产生称为ER应激的条件。长期的内质网应激与高血压有关。延髓头端腹外侧区（RVLM）的氧化应激在神经源性高血压中起着关键作用，RVLM是维持血管紧张素的交感前运动神经元的所在地。本研究旨在评价RVLM中内质网应激对氧化应激相关高血压的作用，并阐明其分子机制。葡萄糖调节蛋白78 kDa和蛋白激酶RNA样ER激酶翻译起始因子a磷酸化是ER应激的两个主要蛋白标志物，其表达在RVLM中增加，并先于自发性高血压大鼠高血压表型的发展。在自发性高血压大鼠RVLM中，salubrinal稳定ER应激可促进降压作用，tempol清除活性氧可减轻增强的ER应激。此外，血管紧张素II诱导的氧化应激诱导的RVLM的ER应激，和诱导的RVLM的ER应激的衣霉素诱导血压正常的Wistar-Kyoto大鼠的升压反应。溶酶体相关膜蛋白2和微管相关蛋白1轻链3-II（LC 3-II）的表达所反映的自噬，在自发性高血压大鼠RVLM显着增加，并被salubrinal废除。此外，抑制RVLM中的自噬或沉默LC 3-II基因可导致自发性高血压大鼠的降压作用。这些结果表明，在RVLM的ER应激和自噬的激活的氧化还原敏感的诱导有助于氧化应激相关的神经源性高血压。
Perturbations of proper functions of the endoplasmic reticulum (ER) cause accumulation of misfolded or unfolded proteins in the cell, creating a condition known as ER stress. Prolonged ER stress has been implicated in hypertension. Oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside, plays a pivotal role in neurogenic hypertension. This study aimed to evaluate the contribution of ER stress in RVLM to oxidative stress-associated hypertension and delineate the underlying molecular mechanisms. The expression of glucose-regulated protein 78 kDa and the phosphorylation of protein kinase RNA-like ER kinase-translation initiation factor a, 2 major protein markers of ER stress, were augmented in RVLM and preceded the development of hypertensive phenotype in spontaneously hypertensive rats. In RVLM of spontaneously hypertensive rats, stabilizing ER stress by salubrinal promoted antihypertension, and scavenging the reactive oxygen species by tempol reduced the augmented ER stress. Furthermore, induction of oxidative stress by angiotensin II induced ER stress in RVLM, and induction of ER stress by tunicamycin in RVLM induced pressor response in normotensive Wistar-Kyoto rats. Autophagy, as reflected by the expression of lysosome-associated membrane protein-2 and microtubule-associated protein 1 light chain 3-II (LC3-II), was significantly increased in RVLM of spontaneously hypertensive rats and was abrogated by salubrinal. In addition, inhibition of autophagy or silencing LC3-II gene in RVLM resulted in antihypertension in spontaneously hypertensive rats. These results suggest that redox-sensitive induction of ER stress and activation of autophagy in RVLM contribute to oxidative stress-associated neurogenic hypertension.