The Two fACEs of the Tissue Renin-Angiotensin Systems: Implication in Cardiovascular Diseases

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.