Lower blood pressure in floxed angiotensinogen mice after adenoviral delivery of Cre-recombinase.
Lower blood pressure in floxed angiotensinogen mice after adenoviral delivery of Cre-recombinase.
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腺病毒递送 Cre 重组酶后，floxed 血管紧张素原小鼠的血压降低。
DOI：
10.1161/hy0202.103418
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Sigmund,CurtD
中科院分区：
文献类型：
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作者：
Stec,DavidE;Keen,HenryL;Sigmund,CurtD
最近的实验证据表明，组织中的肾素-血管紧张素系统在高血压的发展中的作用。为了测试组织中的肾素-血管紧张素系统在血管紧张素II依赖性高血压的发展和维持中的重要性，我们产生了一个转基因模型，其中人血管紧张素原基因的外显子2两侧是loxP位点（hAGTflox），因此该基因的该区域可以被cre重组酶删除。两个独立系的双转基因人肾素和hAGTflox（R+/A+flox）小鼠表现出血压升高。急性施用含有cre重组酶（Adcre）的腺病毒在4天的时间内使血压降低30 mm Hg，如用流体填充的导管测量的。在另一组R+/A+小鼠中通过无线电遥测测定Adcre给药对血压的慢性影响。到Adcre后第8天，血压较基线下降25 mm Hg，但此后每天都升高，直到Adcre后第21天达到基线的90%。表达分析表明在Adcre后第5天肝脏中没有可检测到的hAGT mRNA，但在Adcre后第14至21天重新出现在正常水平。这些研究表明，Adcre对肝脏hAGT的急性消除有效，但对慢性消除无效。肝脏hAGT的慢性消除可能需要使用在肝脏中内源性表达cre重组酶的转基因小鼠。
Recent experimental evidence suggests a role for tissue renin-angiotensin systems in the development of hypertension. To test the importance of tissue renin-angiotensin systems in the development and maintenance of angiotensin II-dependent hypertension, we generated a transgenic model in which exon 2 of the human angiotensinogen gene is flanked by loxP sites (hAGTflox) so that this region of the gene can be deleted by the cre-recombinase. Double transgenic human renin and hAGTflox(R+/A+flox) mice of two independent lines exhibited elevated blood pressure. Acute administration of an adenovirus containing cre-recombinase (Adcre) lowered blood pressure by 30 mm Hg over a 4-day period as measured with fluid filled catheters. The chronic effect of Adcre administration on blood pressure was determined by radiotelemetry in a separate group of R+/A+floxmice. Blood pressure decreased by 25 mm Hg from baseline by day 8 post-Adcre, but increased on each day thereafter until it was 90% of baseline by day 21 post-Adcre. Expression analysis indicated the absence of detectable hAGT mRNA in the liver at day 5 post-Adcre, but reappeared at normal levels at days 14 to 21 post-Adcre. These studies suggest that Adcre is effective for acute, but not chronic, elimination of hepatic hAGT. Chronic elimination of hepatic hAGT will likely require the use of transgenic mice endogenously expressing cre-recombinase in the liver.