Oudit Gavin Y, Crackower Michael A, Backx Peter H, Penninger Josef M
Department of Medical Biophysics and Richard Lewar/Heart and Stroke Center of Excellence, University of Toronto, Toronto, Canada.
Trends Cardiovasc Med. 2003 Apr;13(3):93-101. doi: 10.1016/s1050-1738(02)00233-5.
The renin-angiotensin system (RAS) is critically involved in cardiovascular and renal function and in disease conditions, and has been shown to be a far more complex system than initially thought. A recently discovered homologue of angiotensin-converting enzyme (ACE)--ACE2--appears to negatively regulate the RAS. ACE2 cleaves Ang I and Ang II into the inactive Ang 1-9 and Ang 1-7, respectively. ACE2 is highly expressed in kidney and heart and is especially confined to the endothelium. With quantitative trait locus (QTL) mapping, ACE2 was defined as a QTL on the X chromosome in rat models of hypertension. In these animal models, kidney ACE2 messenger RNA and protein expression were markedly reduced, making ACE2 a candidate gene for this QTL. Targeted disruption of ACE2 in mice failed to elicit hypertension, but resulted in severe impairment in myocardial contractility with increased angiotensin II levels. Genetic ablation of ACE in the ACE2 null mice rescued the cardiac phenotype. These genetic data show that ACE2 is an essential regulator of heart function in vivo. Basal renal morphology and function were not altered by the inactivation of ACE2. The novel role of ACE2 in hydrolyzing several other peptides-such as the apelin peptides, opioids, and kinin metabolites-raises the possibility that peptide systems other than angiotensin and its derivatives also may have an important role in regulating cardiovascular and renal function.
肾素-血管紧张素系统（RAS）在心血管和肾功能以及疾病状态中起着关键作用，并且已被证明是一个比最初认为的更为复杂的系统。最近发现的血管紧张素转换酶（ACE）的同源物——ACE2——似乎对RAS起负调节作用。ACE2分别将血管紧张素I（Ang I）和血管紧张素II（Ang II）切割成无活性的血管紧张素1-9（Ang 1-9）和血管紧张素1-7（Ang 1-7）。ACE2在肾脏和心脏中高度表达，尤其局限于内皮细胞。通过数量性状基因座（QTL）定位，在高血压大鼠模型中，ACE2被定义为X染色体上的一个QTL。在这些动物模型中，肾脏ACE2信使核糖核酸（mRNA）和蛋白质表达明显降低，这使得ACE2成为该QTL的候选基因。在小鼠中靶向破坏ACE2未能引发高血压，但导致心肌收缩力严重受损，同时血管紧张素II水平升高。在ACE2基因敲除小鼠中对ACE进行基因消融挽救了心脏表型。这些遗传学数据表明，ACE2是体内心脏功能的重要调节因子。ACE2失活并未改变基础肾脏形态和功能。ACE2在水解其他几种肽（如apelin肽、阿片类物质和激肽代谢产物）方面的新作用增加了一种可能性，即除血管紧张素及其衍生物之外的肽系统在调节心血管和肾功能方面也可能发挥重要作用。
