DELIVERY OF ANGIOTENSIN-II TYPE-1 RECEPTOR ANTISENSE INHIBITS ANGIOTENSIN ACTION IN NEURONS FROM HYPERTENSIVE RAT-BRAIN
DELIVERY OF ANGIOTENSIN-II TYPE-1 RECEPTOR ANTISENSE INHIBITS ANGIOTENSIN ACTION IN NEURONS FROM HYPERTENSIVE RAT-BRAIN
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DOI：
10.1073/pnas.92.7.2914
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发表时间：
1995-03-28
影响因子：
11.1
通讯作者：
RAIZADA, MK
中科院分区：
文献类型：
--
作者：
LU, D;RAIZADA, MK
脑血管紧张素II（AII）1型受体（AT（1）R）表达增加与脑血管紧张素系统过度活跃以及遗传性自发性高血压（SH）大鼠高血压的发生和维持有关。来自心脏调节相关脑区（下丘脑/脑干）的原代培养的神经元细胞模拟成年SH大鼠脑AT（1）R基因表达和AT（1）R功能的增加。在本研究中，它们被用于确定是否AII的细胞作用可以通过使用为中枢神经系统培养开发的逆转录病毒介导的基因递送系统转移AT（1）R反义（AT（1）R.AS）来调节。AII刺激正常血压（Wistar京都）和SH大鼠脑神经元培养物中的去甲肾上腺素（NE）摄取。这种神经调节作用是由AT（1）R亚型介导的，在SH神经元中明显更高，并且与c-fos和NE转运蛋白的mRNA的平行刺激有关。用含有AT（1）R-AS（LNSV-AT（1）R-AS）的逆转录病毒载体感染神经元培养物，可抑制AT（1）R介导的c-fos和NE转运蛋白mRNA的刺激，以及两种品系大鼠的NE摄取;然而，与Wistar京都大鼠脑神经元相比，SH神经元的抑制作用更为明显。SH大鼠脑神经元的更高敏感性进一步由我们的观察得到支持，即不能诱导抑制WKY神经元中AII细胞作用的一定剂量的LNSV-AT（1）R-AS导致显著抑制SH神经元中AII作用。这些观察结果表明，逆转录病毒介导的AT（1）R-AS可用于选择性地控制AII在SH大鼠脑原代神经元培养物中的作用。
Increased brain angiotensin II (AII) type 1 receptor (AT(1)R) expression has been implicated in the hyperactive brain angiotensin system and the development and maintenance of hypertension in the genetically spontaneously hypertensive (SH) rat. Neuronal cells in primary culture from the cardioregulatory-relevant brain areas (hypothalamus/brainstem) mimic increased brain AT(1)R gene expression and AT(1)R function of the adult SH rat. They have been utilized in the present study to determine whether cellular actions of AII could be regulated by the transfer of AT(1)R antisense (AT(1)R.AS) with the use of a retroviral-mediated gene delivery system developed for the central nervous system cultures. AII stimulates norepinephrine (NE) uptake in neuronal cultures of both normotensive (Wistar Kyoto) and SH rat brains. This neuromodulatory action is mediated by the AT(1)R subtype, is significantly higher in SH neurons, and is associated with a parallel stimulation of mRNAs for c-fos and NE transporter. Infection of neuronal cultures with a retrovirus vector that contains AT(1)R-AS (LNSV-AT(1)R-AS) results in an inhibition of AT(1)R-mediated stimulation of both c-fos and NE transporter mRNA, as well as NE uptake in both strains of rats; however, the inhibition is more pronounced in SH neurons compared with Wistar Kyoto rat brain neurons. The higher sensitivity of the SH rat brain neurons is further supported by our observation that a certain dose of LNSV-AT(1)R-AS that fails to induce inhibition of cellular actions of AII in WKY neurons causes a significant inhibition of AII actions in SH neurons. These observations show that retrovirally mediated delivery of AT(1)R-AS could be used to selectively control the actions of AII in primary neuronal cultures from SH rat brain.