Smithies O
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 27599-7525, USA.
Hypertension. 1997 Dec;30(6):1318-24. doi: 10.1161/01.hyp.30.6.1318.
Essential hypertension probably results from combinations of genetic variations, not necessarily the same in all afflicted persons, which individually may not cause sufficient deviation from normality to be significantly harmful. Genes contributing to hypertension are being sought by analytic experiments aimed at identifying candidate genes associated or segregating with the phenotype in humans and animals and by synthetic experiments in which changes are made in candidate genes in animals and their effects on blood pressure are determined. We have used gene targeting to vary the amounts of angiotensinogen and angiotensin-converting enzyme (ACE) synthesized from their genes (Agt and Ace). These "gene titration" experiments establish that changes in Agt gene expression cause changes in the blood pressures of mice. Surprisingly, quantitative changes in Ace gene expression over a threefold range do not affect blood pressures. Computer simulations with a simple version of the renin-angiotensin system predict that changes in Agt function alter the steady state levels of both angiotensin I (Ang I) and angiotensin II (Ang II). In contrast, modest changes in Ace function alter Ang I levels considerably but scarcely affect Ang II levels. Simulations over the ranges of ACE levels that can be achieved with ACE inhibitors predict that Ang II levels will decrease only when Ang I levels have plateaued. Comparisons of the computer simulations with our genetic experiments and with prior work of others using wide dose ranges of ACE inhibitor show a satisfactory agreement and help reconcile the apparent contradictions between the genetic and pharmacological experiments.
原发性高血压可能是由多种基因变异组合导致的，在所有患者中这些变异不一定相同，单个变异可能不会导致与正常情况有足够大的偏差而产生显著危害。通过分析实验来寻找导致高血压的基因，这些实验旨在识别与人类和动物表型相关或分离的候选基因，以及通过合成实验，在动物的候选基因中进行改变并确定其对血压的影响。我们利用基因靶向技术来改变从其基因（Agt和Ace）合成的血管紧张素原和血管紧张素转换酶（ACE）的量。这些“基因滴定”实验证实，Agt基因表达的变化会导致小鼠血压的改变。令人惊讶的是，Ace基因表达在三倍范围内的定量变化不会影响血压。用肾素-血管紧张素系统的一个简单版本进行的计算机模拟预测，Agt功能的变化会改变血管紧张素I（Ang I）和血管紧张素II（Ang II）的稳态水平。相比之下，Ace功能的适度变化会显著改变Ang I水平，但几乎不影响Ang II水平。在使用ACE抑制剂可达到的ACE水平范围内进行的模拟预测，只有当Ang I水平达到平稳状态时，Ang II水平才会下降。将计算机模拟与我们的基因实验以及其他人使用宽剂量范围的ACE抑制剂的先前工作进行比较，显示出令人满意的一致性，并有助于调和基因实验和药理学实验之间明显的矛盾。
