Lazartigues Eric, Feng Yumei, Lavoie Julie L
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Curr Pharm Des. 2007;13(12):1231-45. doi: 10.2174/138161207780618911.
The implication of the renin-angiotensin system (RAS) in the regulation of the cardiovascular system has been well known for many years. Accordingly, many pharmaceutical inhibitors have been developed to treat several pathologies, like hypertension and heart failure, and angiotensin converting enzyme (ACE) became one of the major target in the treatment of these cardiovascular diseases. In the last decade however, it has become apparent that the classical view of the RAS was not quite accurate. For instance, ACE has been shown to work not only by generating angiotensin-II but also by interacting with receptors outside the renin-angiotensin system. Moreover, it has been shown that many local RAS are present in different tissues, such as the heart, brain, kidney and vasculature. However, in the past, it was impossible to determine the role of these local systems as they were pharmacologically indistinguishable from the systemic RAS. Hence, in recent years, the development of transgenic animals has allowed us to determine that these local systems are implicated in the roles that had been originally attributed exclusively to the systemic action of the RAS. However, with almost 30% of the medicated hypertensive patients harboring an uncontrolled blood pressure, a need for new drugs and new targets appears necessary. With the new century came the discovery of a new homolog of ACE, called ACE2, and early studies suggest that it may play a pivotal role in the RAS by controlling the balance between the vasoconstrictor effects of angiotensin-II and the vasodilatory properties of the angiotensin(1-7) peptide. Like ACE, ACE2 appears to hydrolyze peptides not related with the RAS and the enzyme has also been identified as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Although the tissue localization of ACE2 was originally though to be very restricted, new studies have emerged showing a more widespread distribution. Therefore, the whole dynamics of the RAS has to be re-evaluated in light of this new information. In this review, we will compare the structures, distributions and properties of ACE and its new homologue in the context of cardiovascular function, focusing on the autocrine/paracrine cardiac and brain renin-angiotensin systems and we will present recent data from the literature and our laboratory offering a new perspective on this potential target for the treatment of cardiovascular diseases.
肾素-血管紧张素系统（RAS）在心血管系统调节中的作用多年来已为人熟知。因此，人们开发了许多药物抑制剂来治疗多种病症，如高血压和心力衰竭，血管紧张素转换酶（ACE）成为治疗这些心血管疾病的主要靶点之一。然而，在过去十年中，经典的RAS观点已明显不准确。例如，已证明ACE不仅通过生成血管紧张素II起作用，还通过与肾素-血管紧张素系统外的受体相互作用起作用。此外，已表明许多局部RAS存在于不同组织中，如心脏、大脑、肾脏和血管系统。然而，过去无法确定这些局部系统的作用，因为它们在药理学上与全身RAS无法区分。因此，近年来，转基因动物的发展使我们能够确定这些局部系统与最初仅归因于RAS全身作用的角色有关。然而，近30%的药物治疗高血压患者血压控制不佳，因此需要新药和新靶点。随着新世纪的到来，发现了一种新的ACE同源物，称为ACE2，早期研究表明它可能通过控制血管紧张素II的血管收缩作用与血管紧张素（1-7）肽的血管舒张特性之间的平衡在RAS中起关键作用。与ACE一样，ACE2似乎也能水解与RAS无关的肽，并且该酶也已被鉴定为严重急性呼吸综合征（SARS）冠状病毒的受体。尽管ACE2的组织定位最初被认为非常局限，但新的研究表明其分布更为广泛。因此，必须根据这些新信息重新评估RAS的整体动态。在这篇综述中，我们将在心血管功能的背景下比较ACE及其新同源物的结构、分布和特性，重点关注自分泌/旁分泌心脏和脑肾素-血管紧张素系统，并将展示来自文献和我们实验室的最新数据，为这一潜在的心血管疾病治疗靶点提供新的视角。
