Sun Zhongjie, Bello-Roufai Mahajoub, Wang Xiuqing
Dept. of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73034, USA.
Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1880-7. doi: 10.1152/ajpheart.01319.2007. Epub 2008 Feb 22.
The objective was to determine whether the mineralocorticoid receptor (MR) plays a role in the initiation and development of cold-induced hypertension (CIH) by testing the hypothesis that the RNA interference (RNAi) inhibition of the MR attenuates CIH. The recombinant adeno-associated virus (AAV) carrying a short-hairpin small-interference RNA for MR (MRshRNA) or a scrambled sequence (ControlshRNA) was constructed. Six groups of albino mice were used (6 mice/group). Three groups were exposed to cold (6.7 degrees C), whereas the remaining three groups were kept at room temperature (RT; warm) as controls. In each temperature condition, three groups received an intravenous injection of MRshRNA, ControlshRNA, or virus-free PBS, respectively, before exposure to cold. The viral complexes (0.35 x 10(11) particles/mouse, 0.5 ml) or PBS (0.5 ml) was delivered into the circulation via the tail vein. The blood pressure (BP) of the mice treated with ControlshRNA or PBS increased significantly during exposure to cold, whereas the BP of the cold-exposed MRshRNA-treated mice did not increase and remained at the level of the control group kept at RT. Thus AAV delivery of MRshRNA prevented the initiation of CIH. MRshRNA significantly attenuated cardiac and renal hypertrophy. MRshRNA decreased the cold-induced increase in MR protein expression to the control level in the hypothalamus, kidneys, and heart, indicating an effective prevention of the cold-induced upregulation of MR. RNAi inhibition of MR resulted in significant decreases in the plasma level of norepinephrine, plasma renin activity, and plasma level of aldosterone in cold-exposed mice. MR played a critical role in the initiation and development of CIH. AAV delivery of MRshRNA may serve as a new approach for the prevention of cold-induced hypertension.
目的是通过检验以下假设来确定盐皮质激素受体（MR）在冷诱导高血压（CIH）的发生和发展中是否起作用：RNA干扰（RNAi）抑制MR可减轻CIH。构建了携带针对MR的短发夹小干扰RNA（MRshRNA）或乱序序列（对照shRNA）的重组腺相关病毒（AAV）。使用六组白化小鼠（每组6只小鼠）。三组暴露于寒冷环境（6.7摄氏度），而其余三组保持在室温（RT；温暖环境）作为对照。在每种温度条件下，三组分别在暴露于寒冷之前接受静脉注射MRshRNA、对照shRNA或无病毒PBS。病毒复合物（0.35×10¹¹颗粒/小鼠，0.5毫升）或PBS（0.5毫升）通过尾静脉注入循环系统。用对照shRNA或PBS处理的小鼠在暴露于寒冷期间血压显著升高，而经MRshRNA处理的寒冷暴露小鼠的血压没有升高，维持在保持在RT的对照组水平。因此，AAV递送MRshRNA可预防CIH的发生。MRshRNA显著减轻心脏和肾脏肥大。MRshRNA将下丘脑、肾脏和心脏中寒冷诱导的MR蛋白表达增加降低到对照水平，表明有效预防了寒冷诱导的MR上调。RNAi抑制MR导致寒冷暴露小鼠的去甲肾上腺素血浆水平、血浆肾素活性和醛固酮血浆水平显著降低。MR在CIH的发生和发展中起关键作用。AAV递送MRshRNA可能成为预防冷诱导高血压的一种新方法。
