Nassar Ibrahim, Schulz Angela, Bernardy Claudia, Garrelds Ingrid M, Plehm Ralph, Huber Matthias, Danser A H Jan, Kreutz Reinhold
Institute of Clinical Pharmacology and Toxicology, Charité Centrum für Thearapieforschung, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Am J Hypertens. 2008 Feb;21(2):200-5. doi: 10.1038/ajh.2007.38. Epub 2008 Jan 3.
To study the regulation of a naturally occurring genetic variant of high angiotensin-converting enzyme (ACE) gene (Ace in rat) expression, i.e., the Ace allele of the normotensive Wistar-Kyoto (WKY) rat, in the hypertensive background of stroke-prone spontaneously hypertensive (SHRSP) rats.
We analyzed a congenic strain termed SHRSP.WKY-Ace derived from SHRSP in which a chromosomal fragment of rat chromosome 10 including Ace was replaced by the WKY locus. We compared blood pressures by radiotelemetry, measured plasma ACE activity, tissue ACE messenger RNA (mRNA) and enzyme activities in lung, kidney, and left ventricle (LV) of the heart in adult animals.
Congenic animals demonstrated a twofold increase in plasma ACE activity in comparison to SHRSP (P < 0.05) and thus similar levels to WKY. The increased tissue expression of ACE mRNA and enzyme activities in lung, kidney, and LV observed in WKY were similarly found in congenic animals when compared to SHRSP (P < 0.05, respectively). Systolic and diastolic blood pressures were not different between congenic and SHRSP animals. Analysis of renin in plasma and angiotensin peptides in LV tissues indicated the induction of compensatory mechanisms by downregulation of renin and angiotensin I (Ang I) concentrations in congenic animals.
We demonstrated that genetically determined high ACE expression linked to WKY Ace remains unchanged in the hypertensive background of SHRSP.WKY-Ace. Our data indicate that buffering mechanisms in the renin-angiotensin system contribute to the finding that the development of spontaneous hypertension is not affected, despite an average twofold higher expression of ACE in congenic animals.
为研究高血管紧张素转换酶（ACE）基因（大鼠中的Ace）自然发生的基因变异体，即正常血压的Wistar-Kyoto（WKY）大鼠的Ace等位基因，在易患中风的自发性高血压（SHRSP）大鼠的高血压背景中的调控情况。
我们分析了一种源自SHRSP的同源基因品系，称为SHRSP.WKY-Ace，其中大鼠10号染色体包含Ace的染色体片段被WKY基因座所取代。我们通过无线电遥测比较了血压，测量了成年动物肺、肾和心脏左心室（LV）中的血浆ACE活性、组织ACE信使核糖核酸（mRNA）和酶活性。
与SHRSP相比，同源基因动物的血浆ACE活性增加了两倍（P < 0.05），因此与WKY水平相似。与SHRSP相比，在同源基因动物中同样发现了WKY中观察到的肺、肾和LV中ACE mRNA组织表达增加和酶活性增加（分别为P < 0.05）。同源基因动物和SHRSP动物之间的收缩压和舒张压没有差异。对血浆肾素和LV组织中血管紧张素肽的分析表明，同源基因动物中肾素和血管紧张素I（Ang I）浓度下调诱导了代偿机制。
我们证明，与WKY Ace相关的基因决定的高ACE表达在SHRSP.WKY-Ace的高血压背景中保持不变。我们的数据表明，肾素-血管紧张素系统中的缓冲机制有助于解释尽管同源基因动物中ACE平均表达高出两倍，但自发性高血压的发展并未受到影响这一发现。
