Not just angiotensinases: new roles for the angiotensin-converting enzymes

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Abstract

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Angiotensin II, the primary bioactive peptide of the RAS, is generated from angiotensin I by angiotensin-converting enzyme (ACE). A homologue of ACE, ACE2, is able to convert angiotensin II to a peptide with opposing effects, angiotensin-(1-7). It is proposed that disturbance of the balance of ACE and ACE2 expression and/or function is important in pathologies in which angiotensin II plays a role. These include cardiovascular and renal disease, lung injury and liver fibrosis. The critical roles of ACE and ACE2 in regulating angiotensin II levels have traditionally focussed attention on their activities as angiotensinases. Recent discoveries, however, have illuminated the roles of these enzymes and of the ACE2 homologue, collectrin, in intracellular trafficking and signalling. This paper reviews the key literature regarding both the catalytic and non-catalytic roles of the angiotensin-converting enzyme gene family.

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Most cited references 54

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The emerging role of ACE2 in physiology and disease †

I Hamming, ME Cooper, BL Haagmans … (2007)

Abstract The renin–angiotensin–aldosterone system (RAAS) is a key regulator of systemic blood pressure and renal function and a key player in renal and cardiovascular disease. However, its (patho)physiological roles and its architecture are more complex than initially anticipated. Novel RAAS components that may add to our understanding have been discovered in recent years. In particular, the human homologue of ACE (ACE2) has added a higher level of complexity to the RAAS. In a short period of time, ACE2 has been cloned, purified, knocked‐out, knocked‐in; inhibitors have been developed; its 3D structure determined; and new functions have been identified. ACE2 is now implicated in cardiovascular and renal (patho)physiology, diabetes, pregnancy, lung disease and, remarkably, ACE2 serves as a receptor for SARS and NL63 coronaviruses. This review covers available information on the genetic, structural and functional properties of ACE2. Its role in a variety of (patho)physiological conditions and therapeutic options of modulation are discussed. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Integrins are transmembrane cell-adhesion molecules that carry signals from the outside to the inside of the cell and vice versa. Like other cell surface receptors, integrins signal in response to ligand binding; however, events within the cell can also regulate the affinity of integrins for ligands. This feature is important in physiological situations such as those in blood, in which cells are always in close proximity to their ligands, yet cell-ligand interactions occur only after integrin activation in response to specific external cues. This review focuses on the mechanisms whereby two key proteins, talin and the kindlins, regulate integrin activation by binding the tails of integrin-beta subunits.

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L Acton, Nisha Philip, Thomas M. Coffman … (2006)

The carboxypeptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). To clarify the physiological roles of ACE2, we generated mice with targeted disruption of the Ace2 gene. ACE2-deficient mice were viable, fertile, and lacked any gross structural abnormalities. We found normal cardiac dimensions and function in ACE2-deficient animals with mixed or inbred genetic backgrounds. On the C57BL/6 background, ACE2 deficiency was associated with a modest increase in blood pressure, whereas the absence of ACE2 had no effect on baseline blood pressures in 129/SvEv mice. After acute Ang II infusion, plasma concentrations of Ang II increased almost 3-fold higher in ACE2-deficient mice than in controls. In a model of Ang II-dependent hypertension, blood pressures were substantially higher in the ACE2-deficient mice than in WT. Severe hypertension in ACE2-deficient mice was associated with exaggerated accumulation of Ang II in the kidney, as determined by MALDI-TOF mass spectrometry. Although the absence of functional ACE2 causes enhanced susceptibility to Ang II-induced hypertension, we found no evidence for a role of ACE2 in the regulation of cardiac structure or function. Our data suggest that ACE2 is a functional component of the renin-angiotensin system, metabolizing Ang II and thereby contributing to regulation of blood pressure.

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Author and article information

Contributors

Daniel W. Lambert: d.w.lambert@sheffield.ac.uk

Anthony J. Turner: +44-1133433131 , +44-1133433157 , a.j.turner@leeds.ac.uk

Journal

Journal ID (nlm-ta): Cell Mol Life Sci

Journal ID (iso-abbrev): Cell. Mol. Life Sci

Title: Cellular and Molecular Life Sciences

Publisher: SP Birkhäuser Verlag Basel (Basel )

ISSN (Print): 1420-682X

ISSN (Electronic): 1420-9071

Publication date (Electronic): 10 September 2009

Publication date (Print): 2010

Volume: 67

Issue: 1

Pages: 89-98

Affiliations

[1 ]GRID grid.11835.3e, ISNI 0000000419369262, Oral and Maxillofacial Pathology, Faculty of Medicine, Dentistry and Health, , University of Sheffield, ; S10 2TA Sheffield, UK

[2 ]GRID grid.9909.9, ISNI 0000000419368403, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, , University of Leeds, ; LS2 9JT Leeds, UK

Article

Publisher ID: 152

DOI: 10.1007/s00018-009-0152-x

PMC ID: 7079792

PubMed ID: 19763395

SO-VID: 67831ae6-2b8b-44ad-b838-f716fb69e40c

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.