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. 2003;10(5):377–385. doi: 10.1007/BF02442567

Angiotensin converting enzyme-2 (ACE2) and its possible roles in hypertension, diabetes and cardiac function

Fiona J Warner 1,2,✉, Jodie L Guy 2, Dan W Lambert 2, Nigel M Hooper 2, Anthony J Turner 2
PMCID: PMC7087859  PMID: 32214680

Summary

Angiotensin converting enzyme-2 (ACE2) is a recently described homologue of the vasoactive peptidase, angiotensin converting enzyme (ACE). Like ACE, ACE2 is an integral (type I) membrane zinc metallopeptidase, which exists as an ectoenzyme. ACE2 is less widely distributed than ACE in the body, being expressed at highest concentrations in the heart, kidney and testis. ACE2 also differs from ACE in its substrate specificity, functioning exclusively as a carboxypeptidase rather than a peptidyl dipeptidase. A key role for ACE2 appears to be emerging in the conversion of angiotensin II to angiotensin (1–7), allowing it to act as a counter-balance to the actions of ACE. ACE2 has been localised to the endothelial and epithelial cells of the heart and kidney where it may have a role at the cell surface in hydrolysing bioactive peptides such as angiotensin II present in the circulation. A role for ACE2 in the metabolism of other biologically active peptides also needs to be considered. ACE2 also serendipitously appears to act as a receptor for the severe acute respiratory syndrome (SARS) coronavirus. Studies usingace2 −/− mice, and other emerging studiesin vivo andin vitro, have revealed that ACE2 has important functions in cardiac regulation and diabetes. Together with its role as a SARS receptor, ACE2 is therefore likely to be an important therapeutic target in a diverse range of disease states.

Key words: ACE2, angiotensin-converting enzyme, apelin, diabetes, bradykinin, heart, hypertension, kidney, renin-angiotensin, SARS

Abbreviations

ACE

angiotensin-converting enzyme

ACE2

angiotensin-converting enzyme-2; Ang, angiotensin

APJ

apelin receptor

AT1, AT2

AT4 (angiotensin receptor type 1,2,4)

BK

bradykinin

HEK

Human embryonic kidney

HIV

human immunodeficiency virus

QTL

quantitative trait locus

RAS

renin-angiotensin system

SARS

severe acute respiratory syndrome

SHR

spontaneously hypertensive rat

SHRSP

spontaneously hypertensive rat (stroke-prone)

References

  • 1.Weir M.R. Am. J. Hyp. 1999;12:170S. doi: 10.1016/s0895-7061(99)00219-8. [DOI] [PubMed] [Google Scholar]
  • 2.Fox K.M. Lancet. 2003;362:782–782. doi: 10.1016/S0140-6736(03)14974-4. [DOI] [PubMed] [Google Scholar]
  • 3.Acharya K.R., Sturrock E.D., Riordan J.F., Ehlers M.R.W. Nature Rev. Drug Discov. 2003;2:891–891. doi: 10.1038/nrd1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Anderson S., Rennke H.G., Brenner B.M. J. Clin. Invest. 1986;77:1925–1925. doi: 10.1172/JCI112528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Raij L. Am. J. Hypertens. 2003;16:46–46. doi: 10.1016/j.amjhyper.2003.07.006. [DOI] [PubMed] [Google Scholar]
  • 6.Timmermans P.B., Benfield P., Chiu A.T., Herblin W.F., Wong P.C., Smith R.D. Am. J. Hypertens. 1992;5:221S. doi: 10.1093/ajh/5.12.221s. [DOI] [PubMed] [Google Scholar]
  • 7.Ardaillou R. Curr. Opin. Nephrol. Hypertens. 1997;6:28–28. doi: 10.1097/00041552-199701000-00006. [DOI] [PubMed] [Google Scholar]
  • 8.Tipnis S.R., Hooper N.M., Hyde R., Karran E., Christie G., Turner A.J. J. Biol. Chem. 2000;275:33238–33238. doi: 10.1074/jbc.M002615200. [DOI] [PubMed] [Google Scholar]
  • 9.Donoghue M., Hsieh F., Baronas E., Godbout K., Gosselin M., Stagliano N., Donovan M., Woolf B., Robinson K., Jeyasselan R., Breitbart R.E., Acton S. Circ. Res. 2000;87:E1–E1. doi: 10.1161/01.res.87.5.e1. [DOI] [PubMed] [Google Scholar]
  • 10.Li W., Moore M.J., Vasilieva N., Sui J., Wong S.K., Berne M.A., Somasundaran M., Sullivan J.L., Luzuriaga K., Greenough T.C., Choe H., Farzan M. Nature. 2003;426:450–450. doi: 10.1038/nature02145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Harmer D., Gilbert M., Borman R., Clark K.L. FEBS Lett. 2002;532:107–107. doi: 10.1016/S0014-5793(02)03640-2. [DOI] [PubMed] [Google Scholar]
  • 12.Hooper N.M., Keen J.M., Pappin D.J.C., Turner A.J. Biochem. J. 1987;247:85–85. doi: 10.1042/bj2470085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Vickers C., Hales P., Kaushik V., Dick L., Gavin J., Tang J., Godbout K., Parsons T., Baronas E., Hsieh F., Acton S., Patane M., Nichols A., Tummino P. J. Biol. Chem. 2002;277:14838–14838. doi: 10.1074/jbc.M200581200. [DOI] [PubMed] [Google Scholar]
  • 14.Guy J.L., Jackson R.M., Acharya K.R., Sturrock E.D., Hooper N.M., Turner A.J. Biochemistry. 2003;42:13185–13185. doi: 10.1021/bi035268s. [DOI] [PubMed] [Google Scholar]
  • 15.Turner A.J., Hooper N.M. TiPS. 2002;23:177–177. [Google Scholar]
  • 16.Rice, G.I., Thomas, D.A., Grant, P.J., Turner, A.J. and Hooper, N.M., Biochem. J. (2004) in press. [DOI] [PMC free article] [PubMed]
  • 17.Dales N.A., Gould A.E., Brown J.A., Calderwood E.F., Guan B., Minor C.A., Gavin J.M., Hales P., Kaushik V.K., Stewart M., Tummino P.J., Vickers C.S., Ocain T.D., Patane M.A. J. Am. Chem. Soc. 2002;124:11852–11852. doi: 10.1021/ja0277226. [DOI] [PubMed] [Google Scholar]
  • 18.Huang L., Sexton D.J., Skogerson K., Devlin M., Smith R., Sanyal I., Parry I., Kent R., Enright J., Wu Q.L., Conley G., DeOliveira D., Morganelli L., Ducar M., Westcott C.R., Ladner R.C. J. Biol. Chem. 2003;278:15532–15532. doi: 10.1074/jbc.M212934200. [DOI] [PubMed] [Google Scholar]
  • 19.Towler P., Staker B., Prasad S.G., Menon S., Tang J., Parsons T., Ryan D., Fisher M., Williams D., Dales N.A., Patane M.A., Pantoliano M.W. J. Biol. Chem. 2004;279:17996–17996. doi: 10.1074/jbc.M311191200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Natesh R., Schwager S.L., Sturrock E.D., Acharya K.R. Nature. 2003;421:551–551. doi: 10.1038/nature01370. [DOI] [PubMed] [Google Scholar]
  • 21.Rousseau A., Michaud A., Chauvet M.T., Lenfant M., Corvol P. J. Biol. Chem. 1995;270:3656–3656. doi: 10.1074/jbc.270.8.3656. [DOI] [PubMed] [Google Scholar]
  • 22.Zisman L.S., Keller R.S., Weaver B., Quishan L., Speth R., Bristow M.R., Canver C.C. Circulation. 2003;108:1707–1707. doi: 10.1161/01.CIR.0000094734.67990.99. [DOI] [PubMed] [Google Scholar]
  • 23.Zisman L.S., Meixell G.E., Bristow M.R., Canver C.C. Circulation. 2003;108:1679–1679. doi: 10.1161/01.CIR.0000094733.61689.D4. [DOI] [PubMed] [Google Scholar]
  • 24.Ferrario C.M. Hypertension. 2003;41:390–390. doi: 10.1161/01.HYP.0000060688.57053.7E. [DOI] [PubMed] [Google Scholar]
  • 25.Santos R.A.S., Campagnole-Santos M.J., Andrade S.P. Regul. Pep. 2000;91:45–45. doi: 10.1016/S0167-0115(00)00138-5. [DOI] [PubMed] [Google Scholar]
  • 26.Freeman E.J., Chisholm G.M., Ferrario C.M., Tallant E.A. Hypertension. 1996;28:104–104. doi: 10.1161/01.hyp.28.1.104. [DOI] [PubMed] [Google Scholar]
  • 27.Machado R.D.P., Santos R.A.S., Andrade S.P. Life Sci. 1999;66:67–67. doi: 10.1016/S0024-3205(99)00562-7. [DOI] [PubMed] [Google Scholar]
  • 28.Britto R.R., Santos R.A.S., Fagundes-Moura C.R., Khosla M.C., Campagnole-Santos M.J. Hypertension. 1997;30:549–549. doi: 10.1161/01.hyp.30.3.549. [DOI] [PubMed] [Google Scholar]
  • 29.Paula R.D., Lima C.V., Britto R.R., Campagnole-Santos M.J., Khosla M.C., Santos R.A.S. Peptides. 1999;20:493–493. doi: 10.1016/S0196-9781(99)00031-5. [DOI] [PubMed] [Google Scholar]
  • 30.Brosnihan K.B., Li P., Ferrario C.M. Hypertension. 1996;27:523–523. doi: 10.1161/01.hyp.27.3.523. [DOI] [PubMed] [Google Scholar]
  • 31.Benter I.F., Diz D.I., Ferrario C.M. Peptides. 1993;14:679–679. doi: 10.1016/0196-9781(93)90097-Z. [DOI] [PubMed] [Google Scholar]
  • 32.Deddish P.A., Marcic B., Jackman H.L., Wang H.Z., Skidgel A.R., Erdös E.G. Hypertension. 1998;31:912–912. doi: 10.1161/01.hyp.31.4.912. [DOI] [PubMed] [Google Scholar]
  • 33.Ambühl P., Felix D., Imboden H., Khosla M.C., Ferrario C.M. Regul. Rept. 1992;38:111–111. doi: 10.1016/0167-0115(92)90049-z. [DOI] [PubMed] [Google Scholar]
  • 34.Silva L.C.S., Fontes M.A.P., Campagnole-Santos M.J., Khosla M.C., Campos R.R., Jr., Guertzenstein P.G., Santos R.A.S. Brain Res. 1993;613:321–321. doi: 10.1016/0006-8993(93)90920-I. [DOI] [PubMed] [Google Scholar]
  • 35.Gironacci M.M., Adler-Graschinsky E., Peña C., Enero M.A. Hypertension. 1994;24:457–457. doi: 10.1161/01.hyp.24.4.457. [DOI] [PubMed] [Google Scholar]
  • 36.Vauquelin G., Michotte Y., Smolders I., Sarre S., Ebinger G., Dupont A., Vanderheyden P. J. Renin-Angio.-Aldo. System. 2002;3:195–195. doi: 10.3317/jraas.2002.041. [DOI] [PubMed] [Google Scholar]
  • 37.Trachte G.J., Meixner K., Ferrario C.M., Khosla M.C. Prostaglandins. 1990;39:385–385. doi: 10.1016/0090-6980(90)90120-K. [DOI] [PubMed] [Google Scholar]
  • 38.Fontes M.A., Baltatu O., Caligiorne S.M., Campagnole-Santos M.J., Ganten D., Bader M., Santos R.A. Physiol. Genomics. 2000;2:137–137. doi: 10.1152/physiolgenomics.2000.2.3.137. [DOI] [PubMed] [Google Scholar]
  • 39.Santos R.A.S., Simoes e Silva A.C., Maric C., Silva D.M., Machado R.P., de Buhr I., Heringer-Walther S., Pinheiro S.V., Lopes M.T., Bader M., Mendes E.P., Lemos V.S., Campagnole-Santos M.J., Schultheiss H.P., Speth R., Walther T. Proc. Natl. Acad. Sci. USA. 2003;100:8258–8258. doi: 10.1073/pnas.1432869100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Kohara K., Brosnihan K.B., Ferrario C.M. Peptides. 1993;14:883–883. doi: 10.1016/0196-9781(93)90063-M. [DOI] [PubMed] [Google Scholar]
  • 41.Luque M., Martin P., Martell N., Fernandez C., Brosnihan K.B., Ferrario C.M. J. Hyper. 1996;14:799–799. doi: 10.1097/00004872-199606000-00017. [DOI] [PubMed] [Google Scholar]
  • 42.Ferrario C.M., Martell N., Yunis C., Flack J.M., Chappell M.C., Brosnihan K.B., Dean R.H., Ferandez A., Novikov S.V., Pinillas C., Luque M. Am. J. Hyper. 1998;11:137–137. doi: 10.1016/S0895-7061(97)00400-7. [DOI] [PubMed] [Google Scholar]
  • 43.Crackower M.A., Sarao R., Oudit G.Y., Yagil C., Kozieradzki I., Scanga S.E., Oliveira-dos-Santos A.J., da Costa J., Zhang L., Pei Y., Scholey J., Ferrario C.M., Manoukian A.S., Chappell M.C., Backx P.H., Yagil Y., Penninger J.M. Nature. 2003;417:822–822. doi: 10.1038/nature00786. [DOI] [PubMed] [Google Scholar]
  • 44.Yagil Y., Yagil C. Hypertension. 2003;41:871–871. doi: 10.1161/01.HYP.0000063886.71596.C8. [DOI] [PubMed] [Google Scholar]
  • 45.Chen A.A., Barnes G., Foti A., Nolin E., Lewitzsky S., Metivier J., Meyer J., Parker A., Topol E. Gen. Epidem. 2002;23:272–272. [Google Scholar]
  • 46.Allred A.J., Donoghue M., Acton S., Coffman T.M. Am. J. Nephrol. 2002;13:52A–52A. [Google Scholar]
  • 47.Tatemoto K., Takayama K., Zou M.X., Kumaki I., Zhang W., Kumano K., Fujimiya M. Regul. Pept. 2001;99:87–87. doi: 10.1016/S0167-0115(01)00236-1. [DOI] [PubMed] [Google Scholar]
  • 48.Taheri S., Murphy K., Cohen M., Sujkovic E., Kennedy A., Dhillo W., Dakin C., Sajedi A., Ghatei M., Bloom S. Biochem. Biophys. Res. Comm. 2002;291:1208–1208. doi: 10.1006/bbrc.2002.6575. [DOI] [PubMed] [Google Scholar]
  • 49.Tatemoto K., Hosoya M., Habata Y., Fujii R., Kakegawa T., Zou M.X., Kawamata Y., Fukusumi S., Hinuma S., Kitada C., Kurokawa T., Onda H., Fujino M. Biochem. Biophys. Res. Commun. 1998;251:471–471. doi: 10.1006/bbrc.1998.9489. [DOI] [PubMed] [Google Scholar]
  • 50.Chappell M.C., Jung F., Gallagher P.E., Averill D.B., Crackower M.A., Penninger J.M., Ferrario C.M. Hypertension. 2002;40:83–83. doi: 10.1161/01.HYP.0000022880.45113.C9. [DOI] [PubMed] [Google Scholar]
  • 51.Tikellis C., Johnston C.I., Forbes J.M., Burns W.C., Burrell L.M., Risvanis J., Cooper M.E. Hypertension. 2003;41:392–392. doi: 10.1161/01.HYP.0000060689.38912.CB. [DOI] [PubMed] [Google Scholar]
  • 52.Brosnihan K.B., Neves L.A.A., Joyner J., Averill D.B., Chappell M.C., Sarao R., Penninger J., Ferrario C.M. Hypertension. 2003;42:749–749. doi: 10.1161/01.HYP.0000085220.53285.11. [DOI] [PubMed] [Google Scholar]
  • 53.Anderson S., Jung F.F., Ingelfinger J.R. Am. J. Physiol. 1993;265:F477–F477. doi: 10.1152/ajprenal.1993.265.4.F477. [DOI] [PubMed] [Google Scholar]
  • 54.Mizuiri S., Yoshikawa H., Tanegashima M., Miyagi M., Kobayashi M., Sakai K., Hayashi I., Aikawa A., Ohara T., Hasegawa A. Am. J. Kidney Dis. 1998;31:301–301. doi: 10.1053/ajkd.1998.v31.pm9469501. [DOI] [PubMed] [Google Scholar]
  • 55.Carey R.M., Siragy H.M. Trends Endocrin Met. 2003;14:274–274. doi: 10.1016/S1043-2760(03)00111-5. [DOI] [PubMed] [Google Scholar]
  • 56.Garg R., Yusuf S. J. Am. Med. Assoc. 1995;273:1450–1450. doi: 10.1001/jama.273.18.1450. [DOI] [Google Scholar]
  • 57.Oudit G.Y., Crackower M.A., Backx P.H., Penninger J.M. Trends in Cardiovasc Med. 2003;13:93–93. doi: 10.1016/S1050-1738(02)00233-5. [DOI] [PubMed] [Google Scholar]
  • 58.Huggins C.E., Domenighetti A.A., Pedrazzini T., Pepe S., Delbridge L.M. J. Renin Angiotensin Aldersterone Syst. 2003;4:186–186. doi: 10.3317/jraas.2003.030. [DOI] [PubMed] [Google Scholar]
  • 59.Blaufarb I.S., Sonnenblick E.H. Am. J. Cardiol. 1996;77:8C–8C. doi: 10.1016/S0002-9149(96)00183-X. [DOI] [PubMed] [Google Scholar]
  • 60.Donoghue M., Wakimoto H., Maguire C.T., Acton S., Hales P., Stagliano N., Fairchild-Huntress V., Xu J., Lorenz J.N., Kadambi V., Berul C.I., Breitbart R.E. J. Mol. Cell. Cardiol. 2003;35:1043–1043. doi: 10.1016/S0022-2828(03)00177-9. [DOI] [PubMed] [Google Scholar]
  • 61.Polontchouk L., Ebelt B., Jackels M., Dhein S. FASEB J. 2002;16:87–87. doi: 10.1096/fj.01-0381fje. [DOI] [PubMed] [Google Scholar]
  • 62.Benjafield A.M., Wang W.Y.S., Morris B.J. Am. J. Hyper. 2004;17:624–624. doi: 10.1016/j.amjhyper.2004.02.022. [DOI] [PMC free article] [PubMed] [Google Scholar]

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