Characterization of Angiotensin-(1-7) in the Urine of Normal and Essential Hypertensive Subjects

Ferrario, Carlos M.; Martell, Nieves; Yunis, Carla; Flack, John M.; Chappell, Mark C.; Brosnihan, K. Bridget; Dean, Richard H.; Fernandez, Antony; Novikov, S V; Pinillas, Carmen; Luque, M.E. Ortigosa

doi:10.1016/s0895-7061(97)00400-7

Cited by 107 publications

(91 citation statements)

References 32 publications

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“…These data suggest that Ang-(1-7) exerts only counterregulatory actions on the kidney in response to the activation of the RAS. In humans, urinary Ang-(1-7) was decreased in untreated essential hypertensive patients when compared to normal, healthy individuals (Ferrario et al 1998b). Collectively, these studies show that Ang-(1-7) exerts effects opposite to those of Ang II on the kidney, and that an attenuation of Ang-(1-7) in the kidney may be associated with human hypertension.…”

Section: Physiological Actions Of Ang-(1-7) On the Kidneymentioning

confidence: 67%

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

Trask

Ferrario

2007

Cardiovascular Drug Reviews

101

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Many advances have been made in the cardiovascular field in the last several decades. Among them is the progress completed to date on the heptapeptide member of the reninangiotensin system (RAS), angiotensin-(1-7) [Ang-(1-7)]. The peptide's beneficial actions against pathophysiological processes, such as cardiac arrhythmia, heart failure, hypertension, renal disease, preeclampsia, and even cancer are continuously being uncovered. This review encompasses the pharmacology of Ang-(1-7) and expounds upon the peptide's potential as a therapeutic agent against pathological processes both within and outside the cardiovascular continuum.

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Section: Physiological Actions Of Ang-(1-7) On the Kidneymentioning

confidence: 67%

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

Trask

Ferrario

2007

Cardiovascular Drug Reviews

101

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“…4,5 ACE2 does not act on bradykinins and its activity is not inhibited by ACE inhibitors. 2 Although a significant activation of the RAS system occurs after myocardial infarction, 6 -10 the role of ACE2 and its main products [Ang- (1)(2)(3)(4)(5)(6)(7)(8)(9) and Ang-(1-7)] are still poorly understood. The importance of ACE2 in regulating cardiac function has been implicated by the phenotype of the ACE2 knockout mouse, showing left ventricular dilation, impaired contractility with upregulation of hypoxia-induced genes in the heart, suggesting a link to myocardial ischemia.…”

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confidence: 99%

Enalapril Attenuates Downregulation of Angiotensin-Converting Enzyme 2 in the Late Phase of Ventricular Dysfunction in Myocardial Infarcted Rat

et al. 2006

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Abstract-The early and long-term effects of coronary artery ligation on the plasma and left ventricular angiotensinconverting enzyme (ACE and ACE2) activities, ACE and ACE2 mRNA levels, circulating angiotensin (Ang) levels [Ang I, Ang-(1-7), Ang-(1-9), and Ang II], and cardiac function were evaluated 1 and 8 weeks after experimental myocardial infarction in adult Sprague Dawley rats. Sham-operated rats were used as controls. Coronary artery ligation caused myocardial infarction, hypertrophy, and dysfunction 8 weeks after surgery. At week 1, circulating Ang II and Ang-(1-9) levels as well as left ventricular and plasma ACE and ACE2 activities increased in myocardial-infarcted rats as compared with controls. At 8 weeks post-myocardial infarction, circulating ACE activity, ACE mRNA levels, and Ang II levels remained higher, but plasma and left ventricular ACE2 activities and mRNA levels and circulating levels of Ang-(1-9) were lower than in controls. No changes in plasma Ang-(1-7) levels were observed at any time. Enalapril prevented cardiac hypertrophy and dysfunction as well as the changes in left ventricular ACE, left ventricular and plasmatic ACE2, and circulating levels of Ang II and Ang-(1-9) after 8 weeks postinfarction. Thus, the decrease in ACE2 expression and activity and circulating Ang-(1-9) levels in late ventricular dysfunction post-myocardial infarction were prevented with enalapril. These findings suggest that in this second arm of the renin-angiotensin system, ACE2 may act through Ang-(1-9), rather than Ang-(1-7), as a counterregulator of the first arm, where ACE catalyzes the formation of Ang II. Key Words: angiotensin-converting enzyme Ⅲ myocardial infarction Ⅲ renin-angiotensin system Ⅲ remodeling Ⅲ cardiac function T he renin-angiotensin system (RAS) is a more complex system than originally thought. A new angiotensin-converting enzyme (ACE), ACE2, has been recently identified as a homologue of ACE. 1 ACE2 is also a metalloprotease consisting of 805 amino acids with a considerable degree of homology to ACE (40% identity and 61% similarity). 2,3 ACE2 contains a single zinc-binding domain and is a carboxypeptidase, unlike somatic ACE, which contains 2 zinc-binding domains and is a dipeptidyl carboxypeptidase. 2 Both ACE2 and ACE are bound to the plasma membrane and must be cleaved to release the soluble enzyme. 2 Their cellular and tissue distributions are also different, in that ACE is expressed in the endothelium throughout the vasculature, whereas ACE2 is distributed to most tissues, including to the heart and kidney. 3 Analyses in vitro have shown that ACE2 cleaves angiotensin (Ang) I to Ang-(1-9), which is then cleaved by ACE to Ang-(1-7). However, ACE2 also cleaves Ang II to form Ang-(1-7). Because Ang-(1-7) is a potent vasodepressor peptide, its actions could counterbalance the vasopressor effect of Ang II. 4,5 ACE2 does not act on bradykinins and its activity is not inhibited by ACE inhibitors. 2 Although a significant activation of the RAS system occurs after myocardial infarction, 6 -10 ...

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“…7,9 Thus, in vitro biochemical data suggest that ACE2 negatively regulates Ang II production and function, not only because it decreases local production of Ang II, but also because the cardiovascular effects of its product, Ang (1-7), oppose those of Ang II. 10,11 In addition, there is evidence that other non-ACE enzyme systems may be active in tissue, adding to the local production of Ang II and Ang (1-7). 12,13 Initially, ACE2 appeared to be more limited in its tissue distribution than ACE1, with significant levels detected only in heart, kidney, and testis.…”

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confidence: 99%

New Mass Spectrometric Assay for Angiotensin-Converting Enzyme 2 Activity

et al. 2006

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Abstract-A novel assay was developed for evaluation of mouse angiotensin-converting enzyme (ACE) 2 and recombinant human ACE2 (rACE2) activity. Using surface-enhanced laser desorption/ionization time of flight mass spectrometry (MS) with ProteinChip Array technology, ACE1 and ACE2 activity could be measured using natural peptide substrates.Plasma from C57BL/6 mice, kidney from wild-type and ACE2 knockout mice, and rACE2 were used for assay validation. Plasma or tissue extracts were incubated with angiotensin I (Ang I; 1296 m/z) or angiotensin II (Ang II; 1045 m/z). Reaction mixtures were spotted onto the ProteinChips WCX2 and peptides detected using surface-enhanced laser desorption/ionization time of flight MS. MS peaks for the substrates, Ang I and Ang II, and the generated peptides, Ang (1-7) and Ang (1-9), were monitored. The ACE2 inhibitor MLN 4760 (0.01 to 100 mol/L) significantly inhibited rACE2 activity (IC 50 ϭ3 nmol/L). Ang II was preferably cleaved by rACE2 (kmϭ5 mol/L), whereas Ang I was not a good substrate for rACE2. There was no detectable ACE2 activity in plasma. Assay specificity was validated in a model of ACE2 gene deletion. In kidney extract from ACE2-deficient mice, there was no generation of Ang (1-7) from Ang II. However, Ang (1-7) was produced when Ang I was used as a substrate. In conclusion, we developed a specific and sensitive assay for ACE2 activity, which used the natural endogenous peptide substrate Ang II. This approach allows for the rapid screening for ACE2, which has applications in drug testing, high-throughput enzymatic assays, and identification of novel substrates/inhibitors of the renin-angiotensin system. Key Words: angiotensin Ⅲ renin-angiotensin system Ⅲ mice Ⅲ angiotensin converting enzyme T he renin-angiotensin system (RAS) is a key regulator of cardiovascular and renal function, both under physiological and pathological conditions. 1

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Characterization of Angiotensin-(1-7) in the Urine of Normal and Essential Hypertensive Subjects

Cited by 107 publications

References 32 publications

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

Enalapril Attenuates Downregulation of Angiotensin-Converting Enzyme 2 in the Late Phase of Ventricular Dysfunction in Myocardial Infarcted Rat

New Mass Spectrometric Assay for Angiotensin-Converting Enzyme 2 Activity

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