Keidar Shlomo, Kaplan Marielle, Gamliel-Lazarovich Aviva
The Lipid Research Laboratory, The Bruce Rappaport Faculty of Medicine, Technion, Israel.
Cardiovasc Res. 2007 Feb 1;73(3):463-9. doi: 10.1016/j.cardiores.2006.09.006. Epub 2006 Sep 19.
Angiotensin II (Ang II), a bioactive peptide of the renin-angiotensin system (RAAS), plays an important role in the development of cardiovascular diseases (CVD). Pharmacological inhibition of angiotensin-converting enzyme (ACE), the Ang II forming enzyme, or specific blockade of Ang II binding to angiotensin type 1 receptor (AT1R) through which it exerts its deleterious effects, were shown to provide some protection against progression of CVD. The ACE-Ang II-AT1R axis has been challenged over the last few years with RAAS components able to counterbalance the effects of the main axis. The ACE homologue ACE2 efficiently hydrolyses Ang II to form Ang (1-7), a peptide that exerts actions opposite to those of Ang II. In contrast to the Ang II axis, the role of the ACE2-Ang (1-7) axis in cardiac function is largely obscure. Ang (1-7) is present in the viable myocardium, and its formation depends on Ang II as a substrate. The expression of this peptide is associated with cardiac remodeling: it is lost in the infarcted area and significantly increased in the border area. Low doses of Ang (1-7) improve cardiac output and antagonize Ang II-induced vasoconstriction. The type of Ang (1-7) biological activity is tissue specific and dose dependent. These findings point to a possible protective role for Ang (1-7) in abating the Ang II-induced actions. The elevated expression of Ang (1-7) in failing heart tissue paralleled the expression of its forming enzyme, ACE2. Several observations and experimental evidence suggest a beneficial role for ACE2 in cardiovascular function. Elevated ACE2 expression at the initial stage of several pathologies which decline with progression of disease might indicate a protective role for ACE2. Genetic manipulation of ACE2 expression, either targeted disruption or overexpression, point to the possible significance of this enzyme in cardiac function. Based on the above, a therapeutic approach that will amplify the ACE2-Ang (1-7) axis could provide further protection against the development of CVD. It turns out that the merits of currently used drugs--ACE inhibitors, AT1R blockers and mineralocorticoid receptor blockers (MRB) - lay beyond their direct effects on suppression of the ACE-Ang II-AT1R axis as they also increase cardiac ACE2 and Ang (1-7) significantly.
血管紧张素II（Ang II）是肾素-血管紧张素系统（RAAS）的一种生物活性肽，在心血管疾病（CVD）的发展中起重要作用。血管紧张素转换酶（ACE）是生成Ang II的酶，对其进行药理抑制，或通过特异性阻断Ang II与血管紧张素1型受体（AT1R）的结合（Ang II通过该受体发挥其有害作用），已被证明能为预防CVD进展提供一定保护。在过去几年中，RAAS中能够抵消主轴作用的成分对ACE-Ang II-AT1R轴提出了挑战。ACE的同源物ACE2能有效地将Ang II水解形成血管紧张素（1-7）[Ang (1-7)]，这是一种作用与Ang II相反的肽。与Ang II轴不同，ACE2-Ang (1-7)轴在心脏功能中的作用很大程度上尚不清楚。Ang (1-7)存在于存活的心肌中，其形成依赖于Ang II作为底物。这种肽的表达与心脏重塑有关：它在梗死区域消失，而在边缘区域显著增加。低剂量的Ang (1-7)可改善心输出量并拮抗Ang II诱导的血管收缩。Ang (1-7)生物活性的类型具有组织特异性且依赖剂量。这些发现表明Ang (1-7)在减轻Ang II诱导的作用方面可能具有保护作用。在衰竭心脏组织中Ang (1-7)表达的升高与其生成酶ACE2的表达平行。一些观察结果和实验证据表明ACE2在心血管功能中具有有益作用。在几种疾病的初始阶段ACE2表达升高，但随着疾病进展而下降，这可能表明ACE2具有保护作用。对ACE2表达进行基因操作，无论是靶向破坏还是过表达，都表明这种酶在心脏功能中可能具有重要意义。基于上述情况，一种增强ACE2-Ang (1-7)轴的治疗方法可能为预防CVD的发展提供进一步的保护。事实证明，目前使用的药物——ACE抑制剂、AT1R阻滞剂和盐皮质激素受体阻滞剂（MRB）的优点——不仅仅在于它们对抑制ACE-Ang II-AT1R轴的直接作用，因为它们还能显著增加心脏中的ACE2和Ang (1-7)。
