Angiotensin-converting enzyme 2
Angiotensin converting enzyme 2 (ACE2)[5] is an enzyme attached to the outer surface (cell membranes) of cells in the lungs, arteries, heart, kidney, and intestines.[6][7] ACE2 lowers blood pressure by catalysing the cleavage of angiotensin II (a vasoconstrictor peptide) into angiotensin 1–7 (a vasodilator).[8][9][10] ACE2 also serves as the entry point into cells for some coronaviruses.[5]
ACE2 counters the activity of the related angiotensin-converting enzyme (ACE) by reducing the amount of angiotensin-II and increasing Ang(1-7)[11] making it a promising drug target for treating cardiovascular diseases.[12][13]
ACE2 is a single-pass type I membrane protein, with its enzymatically active domain exposed on the surface of cells in lungs and other tissues.[14] The extracellular domain of ACE2 is cleaved from the transmembrane domain by another enzyme known as sheddase, and the resulting soluble protein is released into the blood stream and ultimately excreted into urine.[15][16]
Coronavirus entry point
As a transmembrane protein, ACE2 serves as the main entry point into cells for some coronaviruses, including HCoV-NL63,[5] SARS-CoV, the virus that causes SARS,[17][18][19] and SARS-CoV-2,[20] the virus that causes COVID-19.[21][22][23][24]
This might lead some to believe that decreasing the levels of ACE2, in cells, might help in fighting the infection. On the other hand, ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.[25]Template:Secondary source required
Furthermore, according to studies conducted on mice, the interaction of the spike protein of the coronavirus with ACE2 induces a drop in the levels of ACE2 in cells through internalization and degradation of the protein and hence may contribute to lung damage.[19][26][27]
Both ACE inhibitors and angiotensin receptor blockers (ARBs) that are used to treat high blood pressure have been shown in a comparative study to upregulate ACE2 expression hence may affect the severity of some other coronavirus infections (e.g., SARS).[28] However, multiple regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.[29] A systematic review and meta-analysis found that "use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls." and "The risk of pneumonia was also reduced in patients treated with ACE inhibitors who were at higher risk of pneumonia, in particular those with stroke and heart failure. Use of ACE inhibitors was also associated with a reduction in pneumonia related mortality, although the results were less robust than for overall risk of pneumonia."[30]
Human recombinant ACE2 (rhACE2)
Human recombinant ACE2 (rhACE2) is surmised to be a novel therapy for acute lung injury, and appeared to improve pulmonary hemodynamics[clarification needed] and oxygen saturation in piglets with a lipopolysaccharide-induced acute respiratory distress syndrome.[31]
The half-life of rhACE2 in human beings is about 10 hours and the onset of action is 30 minutes in addition to the course of effect (duration) of 24 hours.[31]
Several findings suggest that rhACE2 may be a promising drug for those with intolerance to classical RAS inhibitors or in diseases where circulating angiotensin II is elevated.[31]
See also
References
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000015405 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H (June 2004). "Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis". The Journal of Pathology. 203 (2): 631–7. doi:10.1002/path.1570. PMID 15141377.
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- ^ Wang W, McKinnie SM, Farhan M, Paul M, McDonald T, McLean B, et al. (August 2016). "Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System". Hypertension. 68 (2): 365–77. doi:10.1161/HYPERTENSIONAHA.115.06892. PMID 27217402.
- ^ Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. (September 2000). "A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9". Circulation Research. 87 (5): E1–9. doi:10.1161/01.res.87.5.e1. PMID 10969042.
- ^ Chamsi-Pasha MA, Shao Z, Tang WH (March 2014). "Angiotensin-converting enzyme 2 as a therapeutic target for heart failure". Current Heart Failure Reports. 11 (1). Springer Science and Business Media LLC: 58–63. doi:10.1007/s11897-013-0178-0. PMC 3944399. PMID 24293035.
The discovery of ACE2 and its role in counteracting the effect of Ang-II through Ang(1-7) formation...An imbalance in ACE2/Ang-(1–7) and ACE/Ang-II axes is critical in the development of cardiovascular diseases. The central role of ACE2, therefore, appears to counter ACE activity by reducing Ang-II bioavailability and increasing Ang(1-7) formation...The use of RAS-modulating agents and molecules as novel therapeutic agents in hypertension and cardiovascular therapeutic research.
- ^ Chamsi-Pasha MA, Shao Z, Tang WH (March 2014). "Angiotensin-converting enzyme 2 as a therapeutic target for heart failure". Current Heart Failure Reports. 11 (1). Springer Science and Business Media LLC: 58–63. doi:10.1007/s11897-013-0178-0. PMC 3944399. PMID 24293035.
Studies with recombinant human ACE2 (rhACE2) have shown beneficial cardiac effects [18, 36]. rhACE2 has anti-fibrotic properties and can attenuate effect on systolic and diastolic dysfunction, presumably via Ang-II inhibition .
- ^ Mascolo A, Urbanek K, De Angelis A, Sessa M, Scavone C, Berrino L, et al. (March 2020). "Angiotensin II and angiotensin 1-7: which is their role in atrial fibrillation?". Heart Failure Reviews. 25 (2). Springer Science and Business Media LLC: 367–380. doi:10.1007/s10741-019-09837-7. PMID 31375968.
the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.
- ^ Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H (June 2004). "Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis". The Journal of Pathology. 203 (2): 631–7. doi:10.1002/path.1570. PMID 15141377.
- ^ Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, et al. (August 2005). "Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)". The Journal of Biological Chemistry. 280 (34): 30113–9. doi:10.1074/jbc.M505111200. PMID 15983030.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ Patel VB, Clarke N, Wang Z, Fan D, Parajuli N, Basu R, et al. (January 2014). "Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS". Journal of Molecular and Cellular Cardiology. 66: 167–76. doi:10.1016/j.yjmcc.2013.11.017. PMID 24332999.
- ^ Fehr AR, Perlman S (2015). "Coronaviruses: an overview of their replication and pathogenesis". Methods in Molecular Biology. 1282. Springer New York: 1–23. doi:10.1007/978-1-4939-2438-7_1. ISBN 978-1-4939-2437-0. PMC 4369385. PMID 25720466.
Many α-coronaviruses utilize aminopeptidase N (APN) as their receptor, SARS-CoV and HCoV-NL63 use angiotensin-converting enzyme 2 (ACE2) as their receptor, MHV enters through CEACAM1, and the recently identified MERS-CoV binds to dipeptidyl-peptidase 4 (DPP4) to gain entry into human cells (See Table 1 for a list of known CoV receptors).
- ^ Li F (October 2013). "Receptor recognition and cross-species infections of SARS coronavirus". Antiviral Research. 100 (1): 246–54. doi:10.1016/j.antiviral.2013.08.014. PMC 3840050. PMID 23994189.
- ^ a b Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. (August 2005). "A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury". Nature Medicine. 11 (8): 875–9. doi:10.1038/nm1267. PMID 16007097.
- ^ "What are the official names of the disease and the virus that causes it?". Q&A on coronaviruses. World Health Organization. Archived from the original on 5 March 2020. Retrieved 22 February 2020.
- ^ Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. (March 2020). "A pneumonia outbreak associated with a new coronavirus of probable bat origin". Nature. 579 (7798): 270–273. doi:10.1038/s41586-020-2012-7. PMID 32015507.
- ^ Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. (March 2020). "Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission". Science China. Life Sciences. 63 (3): 457–460. doi:10.1007/s11427-020-1637-5. PMID 32009228.
- ^ Lewis, Ricki (2020-02-20). "COVID-19 Vaccine Will Close in on the Spikes". DNA Science Blog. Public Library of Science. Archived from the original on 2020-02-22. Retrieved 2020-02-22.
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suggested) (help) - ^ Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D (2020). "Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein". bioRxiv: 2020.02.19.956581. doi:10.1101/2020.02.19.956581.
- ^ Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et al. (July 2005). "Angiotensin-converting enzyme 2 protects from severe acute lung failure". Nature. 436 (7047): 112–6. Bibcode:2005Natur.436..112I. doi:10.1038/nature03712. PMID 16001071.
- ^ Imai Y, Kuba K, Penninger JM (May 2008). "The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice". Experimental Physiology. 93 (5): 543–8. doi:10.1113/expphysiol.2007.040048. PMID 18448662.
- ^ Jia H (September 2016). "Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease". Shock. 46 (3). Augusta, Ga.: 239–48. doi:10.1097/SHK.0000000000000633. PMID 27082314.
Once SARS-CoV binds to its receptor, the abundance on the cell surface, mRNA expression and the enzymatic activity of ACE2 are significantly reduced. ... These effects are, in part, due to enhanced shedding/internalizing processes. ... The spike protein binds to ACE2 and subsequently down regulated ACE2 protein expression and resulted in worsened acid aspiration pneumonia
- ^ Nicholls J, Peiris M (August 2005). "Good ACE, bad ACE do battle in lung injury, SARS". Nature Medicine. 11 (8): 821–2. doi:10.1038/nm0805-821. PMID 16079870.
- ^ "ESC Says Continue Hypertension Meds Despite COVID-19 Concern". Medscape. Archived from the original on 2020-03-20. Retrieved 2020-03-20.
- ^ Caldeira D, Alarcão J, Vaz-Carneiro A, Costa J (July 2012). "Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis". BMJ. 345 (jul11 1): e4260. doi:10.1136/bmj.e4260. PMC 3394697. PMID 22786934.
Our results suggest an important role of ACE inhibitors, but not ARBs, in reducing the risk of pneumonia. These data may discourage the withdrawal of ACE inhibitors in some patients with tolerable adverse events (namely, cough) who are at particularly high risk of pneumonia. ACE inhibitors also lowered the risk of pneumonia related mortality, mainly in patients with established disease, but the robustness of the evidence was weaker.
- ^ a b c Colafella KM, Uijl E, Danser J (2019). "Interference With the Renin–Angiotensin System (RAS): Classical Inhibitors and Novel Approaches". Encyclopedia of Endocrine Diseases. Elsevier. pp. 523–530. doi:10.1016/b978-0-12-801238-3.65341-2. ISBN 978-0-12-812200-6.
External links
- Human ACE2 genome location and ACE2 gene details page in the UCSC Genome Browser.