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A story of two ACEs

Journal of Molecular Medicine volume 81, pages 227–234 (2003)Cite this article

Abstract

According to the World Health Organization predictions cardiovascular diseases will be the leading cause of death by the year 2020. High blood pressure is a major risk factor for myocardial infarction, cerebrovascular disease, and stroke. Modulation of the renin-angiotensin system, particularly inhibition of the angiotensin-converting enzyme (ACE), has become a prime strategy in the treatment of hypertension and heart failure. Recently the gene of a new ACE, termed ACE2, has been characterized. The ACE2 gene maps to defined quantitative trait loci on the X chromosome in three different rat models of hypertension, suggesting ACE2 as a candidate gene for hypertension. In mice the targeted disruption of ACE2 resulted in increased systemic angiotensin II levels, impaired cardiac contractility, and upregulation of hypoxia-induced genes in the heart. Since mice deficient in both ACE2 and ACE show completely normal heart function, it appears that ACE and ACE2 negatively regulate each other. The mechanisms and physiological significance of the interplay between ACE and ACE2 are not yet elucidated, but it may involve several new peptides and peptide systems. In view of drug development the increasing complexity of the renin-angiotensin system offers both challenge and opportunity to develop new and refined treatment strategies against cardiovascular diseases.

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Abbreviations

ACE :

Angiotensin converting-enzyme

RAS :

Renin-angiotensin system

QTL :

Quantitative trait locus

References

  1. Carretero OA, Oparil S (2000) Essential hypertension. I. Definition and etiology. Circulation 101:329–335

    CAS  PubMed  Google Scholar 

  2. Brilla CG, Myers ZG, Weber KT (1992) Angiotensin II-mediated aldosterone synthesis in cultured bovine aortic cells. J Hypertens 10:S75

    Google Scholar 

  3. Takeda Y, Miyamori I, Yoneda T, Iki K, Hatakeyama H, Blair IA, Hsieh FY, Takeda R (1995) Production of aldosterone in isolated rat blood vessels. Hypertension 2:170–173

    Google Scholar 

  4. Ondetti MA (1991) Angiotensin converting enzyme inhibitors. An overview. Hypertension 18 [Suppl 5]:III134–III135

  5. Cushman DW, Ondetto MA (1999) Design of angiotensin converting enzyme inhibitors. Nat Med 5:1110–1112

    Article  CAS  PubMed  Google Scholar 

  6. Francis GS, Young JB (2001) The looming polypharmacy crisis in the management of patients with heart failure. Potential solutions. Cardiol Clin 19:541–545

    CAS  PubMed  Google Scholar 

  7. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S (2000) A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 87:E1–E9

    CAS  PubMed  Google Scholar 

  8. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ (2000) A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275:33238–33243

    Article  CAS  PubMed  Google Scholar 

  9. Krege JH, John SW, Langenbach LL, Hodgin JB, Hagaman JR, Bachman ES, Jennette JC, O'Brien DA, Smithies O (1995) Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature 375 146–8

    Google Scholar 

  10. Esther CR Jr, Howard TE, Marino EM, Goddard JM, Capecchi MR, Bernstein KE (1996) Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest 74:953–65

    CAS  PubMed  Google Scholar 

  11. Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-Dos-Santos AJ, Da Costa J, Zhang L, Pei Y, Scholey J, Ferrario CM, Manoukian AS, Chappell MC, Backx PH, Yagil Y, Penninger JM (2002) Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417:822–828

    Article  CAS  PubMed  Google Scholar 

  12. Skeggs LT (1956) The preparation and function of the hypertensin converting enzyme J Exp Med 103:295–299

    CAS  Google Scholar 

  13. Turner AJ, Hooper NM (2002) The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 23:177–183

    Article  CAS  PubMed  Google Scholar 

  14. Corvol P, Williams TA (1998) Peptidyl-dipeptidase A/angiotensin I-converting enzyme. In Barrett AJ, et al (eds) Handbook of proteolytical enzymes. Academic, pp 1066–1076

  15. Oppong SY, Hooper NM (1993) Characterization of a secretase activity which releases angiotensin-converting enzyme from the membrane. Biochem J 292:597–603

    CAS  PubMed  Google Scholar 

  16. Esther CR, Marino EM, Howard TE, Machaud A, Corvol P, Capecchi MR, Bernstein KE (1997) The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J Clin Invest 99:2375–2385

    CAS  PubMed  Google Scholar 

  17. Yang HYT (1970) A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochim Biophys Acta 214:374–376

    Article  CAS  PubMed  Google Scholar 

  18. Skidgel RA, Erdoes EG (1985) Novel activity of human angiotensin I converting enzyme: release of the NH2 and COOH terminal tripeptides from the luteinizing hormone-releasing hormone Proc Natl Acad Sci USA 82:1025–1029

    CAS  Google Scholar 

  19. Soubrier F, Alhenc-Gelas F, Hubert C, Allegrini J, John M, Tregear G, Corvol P (1988) Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc Natl Acad Sci U S A 85:9386–9390

    CAS  PubMed  Google Scholar 

  20. Fernandez M, Liu X, Wouters MA, Heyberger S, Husain A (2001) Angiotensin I-converting enzyme transition state stabilization by HIS1089: evidence for a catalytic mechanism distinct from other gluzincin metalloproteinases. J Biol Chem 276:4998–5004

    Article  CAS  PubMed  Google Scholar 

  21. Ehlers MR, Fox EA, Strydom DJ, Riordan JF (1989) Molecular cloning of human testicular angiotensin-converting enzyme: the testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proc Natl Acad Sci U S A 86:7741–7745

    CAS  PubMed  Google Scholar 

  22. Rousseau A, Michaud A, Chauvet MT, Lenfant M, Corvol P (1995) The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensin-converting enzyme. J Biol Chem 270:3656–3661

    CAS  PubMed  Google Scholar 

  23. Perich RB, Jackson B, Rogerson F, Mendelsohn FA, Paxton D, Johnston CI (1992) Two binding sites on angiotensin-converting enzyme: evidence from radioligand binding studies. Mol Pharmacol 42:286–293

    CAS  PubMed  Google Scholar 

  24. Masuell M, Brusca G, Pardo A, Pineiro D, Checkerdhemian S, Forcada P (2002) ACE inhibitors in heart failure–-switching from enalapril to perindopril. Curr Med Res Opin 18:296–302

    Article  PubMed  Google Scholar 

  25. Ruilope LM, Schiffrin EL (2001) Blood pressure control and benefits of antihypertensive therapy: does it make a difference which agents we use? Hypertension 38:537–542

    CAS  PubMed  Google Scholar 

  26. CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316:1429–1435

    Google Scholar 

  27. SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325:293–302

    PubMed  Google Scholar 

  28. Cohn JN, Tognoni G, the Valsartan Heart Failure Trial Investigators (2001) A randomized trial of the angiotensin-receptor blocker Valsartan in chronic heart failure. N Engl J Med 345:1667–1675

    Article  CAS  PubMed  Google Scholar 

  29. Zhang H, Wada J, Hida K, Tsuchiyama Y, Hiragushi K, Shikata K, Wang H, Lin S, Kanwar YS, Makino H (2001) Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J Biol Chem 276:17132–17139

    Article  CAS  PubMed  Google Scholar 

  30. Yagil C, Sapojnikov M, Kreutz R, Zurcher H, Ganten D, Yagil Y (1999) Role of chromosome X in the Sabra rat model of salt-sensitive hypertension. Hypertension 33:261–265

    CAS  PubMed  Google Scholar 

  31. Hilbert P, Lindpaintner K, Beckmann JS, Serikawa T, Soubrier F, Dubay C, Cartwright P, De Gouyon B, Julier C, Takahasi S, et al (1991) Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature 353;521–529

    Google Scholar 

  32. Kloting I, Voigt B, Kovacs P (1998) Metabolic features of newly established congenic diabetes-prone BB.SHR rat strains. Life Sci 62:973–979

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  34. Brosnihan KB, Li P, Tallant EA, Ferrario CM (1998) Angiotensin-(1–7): a novel vasodilator of the coronary circulation. Biol Res 31:227–234

    CAS  PubMed  Google Scholar 

  35. Jackman HL, Massad MG, Sekosan M, Tan F, Brovkovych V, Marcic BM, Erdos EG (2002) Angiotensin 1–9 and 1–7 release in human heart: role of cathepsin A. Hypertension 39:976–981

    Article  CAS  PubMed  Google Scholar 

  36. Iyer SN, Averill DB, Chappell MC, Yamada K, Allred AJ, Ferrario CM (2000) Contribution of angiotensin-(1–7) to blood pressure regulation in salt-depleted hypertensive rats. Hypertension 36:417–422

    CAS  PubMed  Google Scholar 

  37. Ren Y, Garvin JL, Carretero OA (2002) Vasodilator action of angiotensin-(1–7) on isolated rabbit afferent arterioles. Hypertension 39:799–802

    Article  CAS  PubMed  Google Scholar 

  38. Lemos VS, Cortes SF, Silva DM, Campagnole-Santos MJ, Santos RA (2002) Angiotensin 1–7 is involved in the endothelium dependent modulation of phenylephrine-induced contraction in the aorta of mRen-2 transgenic rats. Br J Pharmacol 135:1743–1748

    CAS  PubMed  Google Scholar 

  39. Marceau F, Hess JF, Bachvarov DR (1998) The B1 receptors for kinins. Pharmacol Rev 50:357–386

    CAS  PubMed  Google Scholar 

  40. Duka I, Kintsurashvili E, Gavras I, Johns C, Bresnahan M, Gavras H (2001) Vasoactive potential of the B(1) bradykinin receptor in normotension and hypertension. Circ Res 88:275–281

    CAS  PubMed  Google Scholar 

  41. 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 (2002) Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 277:14838–14843

    Article  CAS  PubMed  Google Scholar 

  42. Hosoya M, Kawamata Y, Fukusumi S, Fujii R, Habata Y, Hinuma S, Kitada C, Honda S, Kurokawa T, Onda H, Nishimura O, Fujino M (2000) Molecular and functional characteristics of APJ Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J Biol Chem 275:21061–21067

    Article  CAS  PubMed  Google Scholar 

  43. Kawamata Y, Habata Y, Fukusumi S, Hosoya M, Fujii R, Hinuma S, Nishizawa N, Kitada C, Onda H, Nishimura O, Fujino M (2001) Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta 1538:162–171

    Article  CAS  PubMed  Google Scholar 

  44. Katugampola SD, Maguire JJ, Kuc RE, Wiley KE, Davenport AP (2002) Discovery of recently adopted orphan receptors for apelin, urotensin II, and ghrelin identified using novel radioligands and functional role in the human cardiovascular system. Can J Physiol Pharmacol 80:369–374

    Article  CAS  Google Scholar 

  45. Tatemoto K, Takayama K, Zou, M. X, Kumaki I, Zhang W, Kumano K, Fujimiya M (2001) The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul Pept 99:87–92

    Article  CAS  PubMed  Google Scholar 

  46. Ventura C, Spurgeon H, Lakatta EG, Guarnieri C, Capogrossi MC (1992) Kappa and delta opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons. Circ Res 70:66–81

    CAS  PubMed  Google Scholar 

  47. Wenzlaff H, Stein B, Teschemacher H (1998) Diminution of contractile response by kappa-opioid receptor agonists in isolated rat ventricular cardiomyocytes is mediated via a pertussis toxin-sensitive G protein. Naunyn Schmiedebergs Arch Pharmacol 358:360–366

    CAS  PubMed  Google Scholar 

  48. Pugsley MK (2002) The diverse molecular mechanisms responsible for the actions of opioids on the cardiovascular system. Pharmacol Ther 93:51–75

    Article  CAS  PubMed  Google Scholar 

  49. Sigmund CD (2001) Genetic manipulation of the renin-angiotensin system in the kidney. Acta Physiol Scand 173:67–73

    Article  CAS  PubMed  Google Scholar 

  50. Hollenberg NK (2001) Renal implications of angiotensin receptor blockers. Am J Hypertens 14:237S–241S

    CAS  PubMed  Google Scholar 

  51. Stec DE, Sigmund CD (2001) Physiological insights from genetic manipulation of the renin-angiotensin system. News Physiol Sci 16:80–84

    Google Scholar 

  52. Bernstein KE (1998) ACE knockout mice—lessons for adult nephrology. Nephrol Dial Transplant 13:2991–2994

    Article  CAS  PubMed  Google Scholar 

  53. Kurokawa K (1998) Tubuloglomerular feedback: its physiological and pathophysiological significance. Kidney Int [Suppl 67]:S71–S74

  54. Yanai K, Saito T, Kakinuma Y, Kon Y, Hirota K, Taniguchi-Yanai K, Nishijo N, Shigematsu Y, Horiguchi H, Kasuya Y, Sugiyama F, Yagami K, Murakami K, Fukamizu A (2000) Renin-dependent cardiovascular functions and renin-independent blood-brain barrier functions revealed by renin-deficient mice. J Biol Chem 275:5–8

    CAS  PubMed  Google Scholar 

  55. Niimura F, Labosky PA, Kakuchi J, Okubo S, Yoshida H, Oikawa T, Ichiki T, Naftilan AJ, Fogo A, Inagami T, et al (1995) Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. J Clin Invest 96:2947–2954

    CAS  PubMed  Google Scholar 

  56. Oliverio MI, Kim HS, Ito M, Le T, Audoly L, Best CF, Hiller S, Kluckman K, Maeda N, Smithies O, Coffman TM (1998) Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II. Proc Natl Acad Sci USA 95:15496–15501

    Google Scholar 

  57. Cole J, Quach du L, Sundaram K, Corvol P, Capecchi MR, Bernstein KE (2002) Mice lacking endothelial angiotensin-converting enzyme have a normal blood pressure. Circ Res 90:87–92

    Article  CAS  PubMed  Google Scholar 

  58. Makino N, Sugano M, Hata T, Taguchi S, Yanaga T (1996) Chronic low-dose treatment with enalapril induced cardiac regression of left ventricular hypertrophy. Mol Cell Biochem 163–164:239–245

    Google Scholar 

  59. Linz W, Wiemer G, Schaper J, Zimmermann R, Nagasawa K, Gohlke P, Unger T, Scholkens BA (1995) Angiotensin converting enzyme inhibitors, left ventricular hypertrophy and fibrosis. Mol Cell Biochem 147–:89–97

  60. Wollert KC, Studer R, von Bulow B, Drexler H (1994) Survival after myocardial infarction in the rat. Role of tissue angiotensin-converting enzyme inhibition. Circulation 90:2457–2467

    CAS  PubMed  Google Scholar 

  61. Kang PM, Landau AJ, Eberhardt RT, Frishman WH (1994) Angiotensin II receptor antagonists: a new approach to blockade of the renin-angiotensin system. Am Heart J 127:1388–1401

    CAS  PubMed  Google Scholar 

  62. Tanimoto K, Sugiyama F, Goto Y, Ishida J, Takimoto E, Yagami K, Fukamizu A, Murakami K (1994) Angiotensinogen-deficient mice with hypotension. J Biol Chem 269:31334–1337

    CAS  PubMed  Google Scholar 

  63. Murphy AM, Kogler H, Georgakopoulos D, McDonough JL, Kass DA, Van Eyk JE, Marban E (2000) Transgenic mouse model of stunned myocardium. Science 287:488–491

    CAS  PubMed  Google Scholar 

  64. Heusch G (1998) Hibernating myocardium. Physiol Rev 78:1055–1085

    CAS  PubMed  Google Scholar 

  65. Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL (2001) HIF-1–dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 61:6669–6673

    CAS  PubMed  Google Scholar 

  66. Kietzmann T, Roth U, Jungermann K (1999) Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood 94:4177–4185

    CAS  PubMed  Google Scholar 

  67. Giordano FJ, Gerber HP, Williams SP, VanBruggen N, Bunting S, Ruiz-Lozano P, Gu Y, Nath AK, Huang Y, Hickey R, Dalton N, Peterson KL, Ross J Jr, Chien KR, Ferrara N (2001) A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc Natl Acad Sci U S A 98:5780–5785

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

U.E. is supported by the Novartis Foundation. J.P. is supported by the Institute for Molecular Biotechnology of the Austrian Academy of Sciences. We thank R. Sarao, G. Oudit, P. Backx and many others for their contributions.

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Affiliations

  1. Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Toronto, Ontario, M5G 2C1, Canada

    Ursula Danilczyk, Urs Eriksson & Josef M. Penninger

  2. Department of Protein Sciences, Amgen Inc., Thousand Oaks, CA 91320, USA

    Michael A. Crackower

  3. Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr Gasse 7, 1030, Vienna, Austria

    Josef M. Penninger

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  1. Ursula Danilczyk
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  2. Urs Eriksson
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  3. Michael A. Crackower
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  4. Josef M. Penninger
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Correspondence to Josef M. Penninger.

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Danilczyk, U., Eriksson, U., Crackower, M.A. et al. A story of two ACEs. J Mol Med 81, 227–234 (2003). https://doi.org/10.1007/s00109-003-0419-x

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Keywords

  • Angiotensin-converting enzyme
  • Angiotensin-converting enzyme 2
  • Knockout mice
  • Renin-angiotensin system