Skip to main content

Advertisement

SpringerLink
Log in

Newly recognized physiologic and pathophysiologic actions of the angiotensin-converting enzyme

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Despite several decades of research into the renin-angiotensin system, new aspects of this endocrine system are elucidated every few years, expanding its role not only in hypertension but also in diabetes, oncology, and cardiology. In this review, we describe newly recognized physiologic actions of the angiotensin-converting enzyme (ACE). These include the role of local versus systemic ACE in maintaining blood pressure, the physiology of bradykinin accumulation during ACE inactivation, and the role of alternate “nonangiotensin” substrates and potential non-enzymatic properties of ACE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Golblatt H, Lynch J, Hanzal RF, Summerville WW: Studies on experimental hypertension. I. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 1934, 59:347–380.

    Article  Google Scholar 

  2. Peach MJ: Renin-angiotensin system: biochemistry and mechanisms of action. Physiol Rev 1977, 57:313–370.

    PubMed  CAS  Google Scholar 

  3. Reid IA, Morris BJ, Ganong WF: The renin-angiotensin system. Annu Rev Physiol 1978, 40:377–410.

    Article  PubMed  CAS  Google Scholar 

  4. Campbell DJ: Circulating and tissue angiotensin systems. J Clin Invest 1987, 79:1–6.

    PubMed  CAS  Google Scholar 

  5. Dostal DE: The cardiac renin-angiotensin system: novel signaling mechanisms related to cardiac growth and function. Regul Pept 2000, 91:1–11.

    Article  PubMed  CAS  Google Scholar 

  6. Leung PS, Carlsson PO: Tissue renin-angiotensin system: its expression, localization, regulation and potential role in the pancreas. J Mol Endocrinol 2001, 26:155–164.

    Article  PubMed  CAS  Google Scholar 

  7. Regoli M, Bendayan M, Fonzi L, et al.: Angiotensinogen localization and secretion in the rat pancreas. J Endocrinol 2003, 179:81–89.

    Article  PubMed  CAS  Google Scholar 

  8. Beldent V, Michaud A, Bonnefoy C, et al.: Cell surface localization of proteolysis of human endothelial angiotensin I-converting enzyme: effect of the amino-terminal domain in the solubilization process. J Biol Chem 1995, 270:28962–28969.

    Article  PubMed  CAS  Google Scholar 

  9. Bernstein KE, Martin BM, Edwards AS, Bernstein EA: Mouse angiotensin-converting enzyme is a protein composed of two homologous domains. J Biol Chem 1989, 264:11945–11951.

    PubMed  CAS  Google Scholar 

  10. Soubrier F, Alhenc-Gelas F, Hubert C, et al.: Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc Natl Acad Sci U S A 1988, 85:9386–9390.

    Article  PubMed  CAS  Google Scholar 

  11. Wei L, Alhenc-Gelas F, Corvol P, Clauser E: The two homologous domains of human angiotensin I-converting enzyme are both catalytically active. J Biol Chem 1991, 266:9002–9008.

    PubMed  CAS  Google Scholar 

  12. Jaspard E, Wei L, Alhenc-Gelas F: Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II): studies with bradykinin and other natural peptides. J Biol Chem 1993, 268:9496–9503.

    PubMed  CAS  Google Scholar 

  13. Cushman DW, Cheung HS: Concentrations of angiotensinconverting enzyme in tissues of the rat. Biochim Biophys Acta 1971, 250:261–265.

    PubMed  CAS  Google Scholar 

  14. El-Dorry HA, Bull HG, Iwata K, et al.: Molecular and catalytic properties of rabbit testicular dipeptidyl carboxypeptidase. J Biol Chem 1982, 257:14128–14133.

    PubMed  CAS  Google Scholar 

  15. Langford KG, Shai SY, Howard TE, et al.: Transgenic mice demonstrate a testis-specific promoter for angiotensinconverting enzyme. J Biol Chem 1991, 266:15559–15562.

    PubMed  CAS  Google Scholar 

  16. Howard T, Balogh R, Overbeek P, Bernstein KE: Sperm-specific expression of angiotensin-converting enzyme (ACE) is mediated by a 91-base-pair promoter containing a CRE-like element. Mol Cell Biol 1993, 13:18–27.

    PubMed  CAS  Google Scholar 

  17. Krege JH, John SW, Langenbach LL, et al.: Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature 1995, 375:146–148.

    Article  PubMed  CAS  Google Scholar 

  18. Esther CR Jr, Howard TE, Marino EM, et al.: Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest 1996, 74:953–965.

    PubMed  CAS  Google Scholar 

  19. Esther CR, Marino EM, Howard TE, et al.: The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J Clin Invest 1997, 99:2375–2385.

    Article  PubMed  CAS  Google Scholar 

  20. Esther CR, Marino EM, Bernstein KE: The role of angiotensinconverting enzyme in blood pressure control, renal function, and male fertility. Trends Endocrinol Metab 1997, 8:181–186.

    Article  CAS  PubMed  Google Scholar 

  21. Nguyen G, Delarue F, Burckle C, et al.: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002, 109:1417–1427.

    Article  PubMed  CAS  Google Scholar 

  22. Xiao HD, Fuchs S, Frenzel K, et al.: Newer approaches to genetic modeling in mice: tissue-specific protein expression as studied using angiotensin-converting enzyme (ACE). Am J Pathol 2003, 163:807–817.

    PubMed  CAS  Google Scholar 

  23. Cole J, Quach DL, Sundaram K, et al.: Mice lacking endothelial angiotensin-converting enzyme have a normal blood pressure. Circ Res 2002, 90:87–92.

    Article  PubMed  CAS  Google Scholar 

  24. Cole JM, Khokhlova N, Sutliff RL, et al.: Mice lacking endothelial ACE: normal blood pressure with elevated angiotensin II. Hypertension 2003, 41:313–321.

    Article  PubMed  CAS  Google Scholar 

  25. Xiao HD, Fuchs S, Cole JM, et al.: Role of bradykinin in angiotensin-converting enzyme knockout mice. Am J Physiol Heart Circ Physiol 2003, 284:H1969-H1977. Double knockout (ACE and bradykinin B2 receptor) mice were investigated. This study showed that the lack of Ang II production, rather than the accumulation of bradykinin, contributed to the ACE knockout phenotype.

    PubMed  CAS  Google Scholar 

  26. Allred AJ, Diz DI, Ferrario CM, Chappell MC: Pathways for angiotensin-(1–7) metabolism in pulmonary and renal tissues. Am J Physiol Renal Physiol 2000, 279:F841-F850.

    PubMed  CAS  Google Scholar 

  27. Donoghue M, Hsieh F, Baronas E, et al.: A novel angiotensinconverting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 2000, 87:E1-E9. The cloning of ACE2, its localization, and catalytic properties are described.

    PubMed  CAS  Google Scholar 

  28. Tipnis SR, Hooper NM, Hyde R, et al.: A human homolog of angiotensin-converting enzyme: cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000, 275:33238–33243. The cloning of ACE2, its localization, and catalytic properties are described.

    Article  PubMed  CAS  Google Scholar 

  29. Danilczyk U, Eriksson U, Crackower MA, Penninger JM: A story of two ACEs. J Mol Med 2003, 81:227–234.

    PubMed  CAS  Google Scholar 

  30. Rousseau A, Michaud A, Chauvet MT, et al.: The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensinconverting enzyme. J Biol Chem 1995, 270:3656–3661.

    Article  PubMed  CAS  Google Scholar 

  31. Rieger KJ, Saez-Servent N, Papet MP, et al.: Involvement of human plasma angiotensin I-converting enzyme in the degradation of the haemoregulatory peptide N-acetyl-seryl-aspartyl-lysylproline. Biochem J 1993, 296:373–378.

    PubMed  CAS  Google Scholar 

  32. Rioli V, Gozzo FC, Heimann AS, et al.: Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme. J Biol Chem 2003, 278:8547–8555. Potential new substrates of ACE were identified and discussed.

    Article  PubMed  CAS  Google Scholar 

  33. Coates D, Isaac RE, Cotton J, et al.: Functional conservation of the active sites of human and Drosophila angiotensin Iconverting enzyme. Biochemistry 2000, 39:8963–8969.

    Article  PubMed  CAS  Google Scholar 

  34. Ekbote U, Looker M, Isaac RE: ACE inhibitors reduce fecundity in the mosquito, Anopheles stephensi. Comp Biochem Physiol B Biochem Mol Biol 2003, 134:593–598.

    Article  PubMed  CAS  Google Scholar 

  35. Coates D: The angiotensin converting enzyme (ACE). Int J Biochem Cell Biol 2003, 35:769–773.

    Article  PubMed  CAS  Google Scholar 

  36. Kohlstedt K, Shoghi F, Muller-Esterl W, et al.: CK2 phosphorylates the angiotensin-converting enzyme and regulates its retention in the endothelial cell plasma membrane. Circ Res 2002, 91:749–756. Studies showed evidences of nonenzymatic properties of ACE involving its short intracellular tail.

    Article  PubMed  CAS  Google Scholar 

  37. Burnett G, Kennedy EP: The enzymatic phosphorylation of proteins. J Biol Chem 1954, 211:969–980.

    PubMed  CAS  Google Scholar 

  38. Skeggs LT Jr, Kahn JR, Shumway NP: The preparation and function of the hypertensin-converting enzyme. J Exp Med 1956, 103:295–299.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Emory University, 101 Woodruff Circle, 30322, Atlanta, GA, USA

    Sebastien Fuchs MD, PhD, Kristen Frenzel PhD, Hong D. Xiao MD, PhD, Jonathan W. Adams MA, Hui Zhao MD, George Keshelava MD, Lu Teng PhD & Kenneth E. Bernstein MD

Authors
  1. Sebastien Fuchs MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristen Frenzel PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong D. Xiao MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan W. Adams MA
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui Zhao MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. George Keshelava MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lu Teng PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kenneth E. Bernstein MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fuchs, S., Frenzel, K., Xiao, H.D. et al. Newly recognized physiologic and pathophysiologic actions of the angiotensin-converting enzyme. Current Science Inc 6, 124–128 (2004). https://doi.org/10.1007/s11906-004-0087-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-004-0087-4

Keywords

Search

Navigation