Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:The two fACEs of the tissue renin-angiotensin systems: implication in cardiovascular diseases. 1750 32

The renin-angiotensin-system (RAS) is a cascade of enzymatic reactions resulting ultimately in the formation of angiotensin II. Recent research has expanded the knowledge about the RAS by adding new components to the pathways: angiotensin-(1-5) [Ang-1-5], angiotensin-(1-7) [Ang-(1-7)], angiotensin-(1-9) [Ang-(1-9)], an ACE homologous enzyme, ACE2, and the G-protein-coupled receptor mas as a molecular receptor for Ang-(1-7). Although previous studies provided some conflicting evidence about the relevance of Ang-(1-7) in the regulation of vascular and renal function, data now demonstrate that Ang-(1-7) contributes to the cardiovascular effects of ACE-inhibitors (ACE-1) and AT1-receptor-blockers (ARBs) both in experimental conditions and in humans. This review summarizes and critically discusses the currently available experimental and clinical study evidence for the role of Ang-(1-7) as a vasodilator and anti-trophic peptide in cardiovascular drug therapy. In addition, the potential therapeutic impact of currently available RAS blocking agents (ACE-1 and ARBs) and new agents still under development (renin-inhibitors) on the RAS-effector peptides is highlighted.
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PMID:Role of the vasodilator peptide angiotensin-(1-7) in cardiovascular drug therapy. 1758 83

There is an increasing body of evidence to suggest that the RAS (renin-angiotensin system) contributes to tissue injury and fibrosis in chronic liver disease. A number of studies have shown that components of a local hepatic RAS are up-regulated in fibrotic livers of humans and in experimental animal models. Angiotensin II, the main physiological effector molecule of this system, mediates liver fibrosis by stimulating fibroblast proliferation (myofibroblast and hepatic stellate cells), infiltration of inflammatory cells, and the release of inflammatory cytokines and growth factors such as TGF (transforming growth factor)-beta1, IL (interleukin)-1beta, MCP (monocyte chemoattractant protein)-1 and connective tissue growth factor. Furthermore, blockade of the RAS by ACE (angiotensin-converting enzyme) inhibitors and angiotensin type 1 receptor antagonists significantly attenuate liver fibrosis in experimental models of chronic liver injury. In 2000 ACE2 (angiotensin-converting enzyme 2), a human homologue of ACE, was identified. ACE2 efficiently degrades angiotensin II to angiotensin-(1-7), a peptide which has recently been shown to have both vasodilatory and tissue protective effects. This suggests that ACE2 and its products may be part of an alternate enzymatic pathway in the RAS, which counterbalances the generation and actions of angiotensin II, the ACE2-angiotensin-(1-7)-Mas axis. This review focuses on the potential roles of the RAS, angiotensin II and ACE2 in chronic liver injury and fibrogenesis.
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PMID:Liver fibrosis: a balance of ACEs? 1760 May 27

A recently discovered homologue of the angiotensin-converting enzyme, ACE2, insensitive to ACE inhibitors, was found in rodents and humans. ACE2 is expressed mainly in the vasculature, heart and kidney. ACE2 removes a single amino acid of the carboxy terminal of peptides. In the renin-angiotensin-aldosterone system (RAAS), it is responsible for the conversion of angiotensin I (Ang I) and angiotensin II (Ang II) to Ang 1-9 and Ang 1-7, respectively. While ACE forms Ang II, a potent vasoconstrictor, ACE2 degrades this peptide to form Ang 1-7 which has an opposite action. Therefore, ACE2 counteracts ACE in the balance of vasopressor/vasodilator as well as heart and kidney function. The importance of ACE2 in physiological and pathophysiological conditions is unclear and is currently being studied.
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PMID:[The importance of ACE2 in regulating the cardiovascular system]. 1796 9

Screening of a metalloprotease library led to the identification of a thiol-based dual ACE/NEP inhibitor as a potent ACE2 inhibitor. Modifications of the P(1) benzyl moiety led to improvements in ACE2 potency as well as to increased selectivity versus ACE and NEP.
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PMID:Thiol-based angiotensin-converting enzyme 2 inhibitors: P1 modifications for the exploration of the S1 subsite. 1807 50

Explorations of the S(1') subsite of ACE2 via modifications of the P(1') methylene biphenyl moiety of thiol-based metalloprotease inhibitors led to improvements in ACE2 selectivity versus ACE and NEP, while maintaining potent ACE2 inhibition.
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PMID:Thiol-based angiotensin-converting enzyme 2 inhibitors: P1' modifications for the exploration of the S1' subsite. 1824 95

Angiotensin (Ang)-converting enzyme 2 (ACE2) metabolizes Ang II to the vasodilatory peptide Ang(1-7), while neprilysin (NEP) generates Ang(1-7) from Ang I. Experiments used novel Surface Enhanced Laser Desorption Ionization-Time of Flight (SELDI-TOF) mass spectroscopic (MS) assays to study Ang processing. Mass spectroscopy was used to measure proteolytic conversion of Ang peptide substrates to their specific peptide products. We compared ACE/ACE2 activity in plasma, brain and kidney from C57BL/6 and NEP(-/-) mice. Plasma or tissue extracts were incubated with Ang I or Ang II (1296 or 1045, m/z, respectively), and generated peptides were monitored with MS. Angiotensin-converting enzyme 2 activity was detected in kidney and brain, but not in plasma. Brain ACE2 activity was highest in hypothalamus. Angiotensin-converting enzyme 2 activity was inhibited by the specific ACE2 inhibitor, DX600 (10 microm, 99% inhibition), but not by the ACE inhibitor, captopril (10 microm). Both MS and colorimetric assays showed high ACE activity in plasma and kidney with low levels in brain. To extend these findings, ACE measurements were made in ACE overexpressing mice. Angiotensin-converting enzyme four-copy mice showed higher ACE activity in kidney and plasma with low levels in hypothalamus. In hypothalamus from NEP-/- mice, generation of Ang(1-7) from Ang I was decreased, suggesting a role for NEP in Ang metabolism. With Ang II as substrate, there was no difference between NEP-/- and wild-type control mice, indicating that other enzymes may contribute to generation of Ang(1-7). The data suggest a predominant role of hypothalamic ACE2 in the processing of Ang II, in contrast to ACE, which is most active in plasma.
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PMID:Brain angiotensin-converting enzymes: role of angiotensin-converting enzyme 2 in processing angiotensin II in mice. 1826 57

In the past few years, the classical concept of the renin-angiotensin system (RAS) has experienced substantial conceptual changes. The identification of: the renin/prorenin receptor; the angiotensin-converting enzyme homologue, ACE2, as an angiotensin peptide-processing enzyme and a virus receptor for severe acute respiratory syndrome, the Mas as a receptor for angiotensin (1-7) [Ang(1-7)], and the possibility of signaling through ACE have contributed to switch our understanding of the RAS from the classical limited-proteolysis linear cascade to a cascade with multiple mediators, multiple receptors and multifunctional enzymes. With regard to Ang(1-7), the identification of ACE2 and of Mas as a receptor implicated in its actions contributed to decisively establish this heptapeptide as a biologically active member of the RAS cascade. In this review, we will focus on the recent findings related to the ACE2-Ang(1-7)-Mas axis and, in particular, on its putative role as an ACE-Ang II-AT(1) receptor counter-regulatory axis within the RAS.
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PMID:Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis. 1831 Feb 57

Angiotensin (Ang) AT1 receptors and Ang-converting enzymes (ACE and ACE2) are expressed in the dorsal vagal complex (DVC) of the brainstem. The aim of this study was to examine in vivo interactions between brainstem Ang AT1 receptors, ACE and ACE2 using small, hairpin RNA (shRNA) gene-silencing methods. The study takes advantage of the bilateral brainstem expression of renin-angiotensin system (RAS) markers. Adenovirus vectors (Ad, 2.0 x 10(9) c.f.u. ml(-1), 200 nl) carrying interference small hairpin RNA (shRNA) for either AngAT1a (Ad-AT1a-shRNA) or AngAT1b (Ad-AT1b-shRNA) were microinjected into the right side of the brainstem DVC. The Ad-LacZ control was injected into the left side. Brainstems were processed with in situ hybridization and immunochemistry. Results showed that: (1) Ad-AT1a-shRNA downregulated Ang AT1a mRNA by 61.2 +/- 6.8% (P < 0.01) and Ad-AT1b-shRNA downregulated Ang AT1b mRNA by 51.6 +/- 5.2% (P < 0.01); (2) downregulation of Ang AT1a mRNA was associated with decreased ACE2 mRNA expression (decrease of 29.0 +/- 14.5%, P < 0.01), while reduction in Ang Ad-AT1b mRNA had no effect; (3) ACE mRNA expression was not altered by either RNA interference (RNAi) treatment; and (4) immunochemical staining for Ang AT1 receptors, ACE and ACE2 were in agreement with the mRNA changes observed. These results demonstrate the utility of in vivo gene silencing to examine functional specificity. Both Ad-AT1a-shRNA and Ad-AT1b-shRNA induced site- and subtype-specific downregulation of receptor expression. Gene silencing showed that there were interactions between brainstem Ang AT1a receptors and the RAS regulatory enzyme, ACE2.
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PMID:RNA interference shows interactions between mouse brainstem angiotensin AT1 receptors and angiotensin-converting enzyme 2. 1831 Feb 59

The renin-angiotensin system (RAS) is a key regulator of vascular resistance, sodium and water homeostasis and the response to tissue injury. Historically, angiotensin II (Ang II) was thought to be the primary effector peptide of this system. Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I). Ang II acts mainly through the angiotensin II type-1 receptor (AT(1)) and, together with ACE, these components represent the 'classical' axis of the RAS. Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. In 2000, two groups using different methodologies identified a homolog of ACE, called ACE2, which cleaves Ang II to form the biologically active heptapeptide, Ang-(1-7). Conceptually, ACE2, Ang-(1-7), and its putative receptor, the mas receptor represent an 'alternative' axis of the RAS capable of opposing the often deleterious actions of Ang II. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang-(1-7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang-(1-7) rather than inhibition of Ang II production or receptor binding. The present review focuses on the novel components and pathways of the RAS with particular reference to their potential contribution towards the pathophysiology of liver disease.
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PMID:Liver disease and the renin-angiotensin system: recent discoveries and clinical implications. 1855


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