Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Yusuf, S., Reddy, S., Ounpuu, S. & Anand, S. Global burden of cardiovascular diseases. Part I: General considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 104, 2746–2753 (2001)

  2. 2

    Carretero, O. A. & Oparil, S. Essential hypertension. Part I: Definition and etiology. Circulation 101, 329–335 (2000)

  3. 3

    Jacob, H. J. Physiological genetics: Application to hypertension research. Clin. Exp. Pharm. Phys. 26, 530–535 (1999)

  4. 4

    Rapp, J. P. Genetic analysis of inherited hypertension in the rat. Physiol. Rev. 80, 135–172 (2000)

  5. 5

    Stoll, M. et al. A genomic-systems biology map for cardiovascular function. Science 294, 1723–1726 (2001)

  6. 6

    Corvol, P. & Williams, T. A. in Handbook of Proteolytic Enzymes (eds Barrett, A. J., Rawlings, N. D. & Woessner, J. F.) 1066–1076 (Academic, London, 1998)

  7. 7

    Skeggs, L. T., Dorer, F. E., Levine, M., Lentz, K. E. & Kahn, J. R. The biochemistry of the renin-angiotensin system. Adv. Exp. Med. Biol. 130, 1–27 (1980)

  8. 8

    Krege, J. H. et al. Male–female differences in fertility and blood pressure in ACE-deficient mice. Nature 375, 146–148 (1995)

  9. 9

    Esther, C. R. et al. Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology and reduced male fertility. Lab. Invest. 74, 953–965 (1996)

  10. 10

    Wuyts, B., Delanghe, J. & De Buyzere, M. Angiotensin I-converting enzyme insertion/deletion polymorphism: clinical implications. Acta Clin. Belg. 52, 338–349 (1997)

  11. 11

    Elkind, M. S. & Sacco, R. L. Stroke risk factors and stroke prevention. Semin. Neurol. 18, 429–440 (1998)

  12. 12

    Hollenberg, N. K. Angiotensin converting enzyme inhibition and the kidney. Curr. Opin. Cardiol. 3 (Suppl. 1), S19–S29 (1988)

  13. 13

    Garg, R. & Yusuf, S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. J. Am. Med. Assoc. 273, 1450–1456 (1995)

  14. 14

    Tipnis, S. R. et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J. Biol. Chem. 275, 33238–33243 (2000)

  15. 15

    Donoghue, M. et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ. Res. 87, e1–e8 (2000)

  16. 16

    Cornell, M. J. et al. Cloning and expression of an evolutionary conserved single-domain angiotensin converting enzyme from Drosophila melanogaster. J. Biol. Chem. 270, 13613–13619 (1995)

  17. 17

    Taylor, C. A., Coates, D. & Shirras, A. D. The Acer gene of Drosophila codes for an angiotensin-converting enzyme homologue. Gene 181, 191–197 (1996)

  18. 18

    Yagil, C. et al. Role of chromosome X in the Sabra rat model of salt-sensitive hypertension. Hypertension 33 Part II, 261–265 (1999)

  19. 19

    Hilbert, P. et al. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature 353, 521–529 (1991)

  20. 20

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

  21. 21

    Koike, G. et al. Cloning, characterization, and genetic mapping of the rat type 2 angiotensin II receptor gene. Hypertension 26, 998–1002 (1995)

  22. 22

    Laragh, J. H. Renovascular hypertension: a paradigm for all hypertension. J. Hypertens. 4 (Suppl. 4), S79–S88 (1986)

  23. 23

    Yagil, C. et al. Development, genotype and phenotype of a new colony of the Sabra hypertension prone (SBH/y) and resistant (SBN/y) rat model of salt sensitivity and resistance. J. Hypertens. 14, 175–182 (1996)

  24. 24

    Tanimoto, K. et al. Angiotensinogen-deficient mice with hypotension. J. Biol. Chem. 269, 31334–31337 (1994)

  25. 25

    Kloner, R. A., Bolli, R., Marban, E., Reinlib, L. & Braunwald, E. Medical and cellular implications of stunning, hibernation, and preconditioning: and NHLBI workshop. Circulation 97, 1848–1867 (1998)

  26. 26

    Murphy, A. M. et al. Transgenic mouse model of stunned myocardium. Science 287, 488–491 (2000)

  27. 27

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

  28. 28

    Sowter, H. M., Ratcliffe, P. J., Watson, P., Greenberg, A. H. & Harris, A. L. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 61, 6669–6673 (2001)

  29. 29

    Kietzmann, T., Roth, U. & Jungermann, K. 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 (1999)

  30. 30

    Giordano, F. J. et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc. Natl Acad. Sci. USA 98, 5780–5785 (2001)

  31. 31

    Spradling, A. C. et al. The Berkeley Drosophila Genome Project gene disruption project: Single P-element insertions mutating 25% of vital Drosophila genes. Genetics 153, 135–177 (1999)

  32. 32

    Frasch, M., Hoey, T., Rushlow, C., Doyle, H. J. & Levine, M. Characterization and localization of the even-skipped protein of Drosophila. EMBO J. 6, 749–759 (1987)

  33. 33

    Azpiazu, N., Lawrence, P., Vincent, J-P. & Frasch, M. Segmentation and specification of the Drosophila mesoderm. Genes Dev. 10, 3183–3194 (1996)

  34. 34

    Zhizhang, Y. & Frasch, M. Regulation and function of tinman during dorsal mesoderm induction and heart specification in Drosophila. Dev. Gen. 22, 187–200 (1998)

  35. 35

    Harvey, R. NK-2 homeobox genes and heart development. Dev. Biol. 178, 203–216 (1996)

  36. 36

    Cai, H. & Harrison, D. G. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ. Res. 87, 840–844 (2000)

  37. 37

    Enseleit, F., Hurlimann, D. & Luscher, T. F. Vascular protective effects of angiotensin converting enzymes inhibitors and their relation to clinical events. J. Cardiovasc. Pharmacol. 37 (Suppl. 1), S21–S30 (2001)

  38. 38

    Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999)

  39. 39

    Wickenden, A. D. et al. Targeted expression of a dominant-negative K(v)4.2 K( + ) channel subunit in the mouse heart. Circ. Res. 85, 1067–1076 (1999)

  40. 40

    Zvaritch, E. et al. The transgenic expression of highly inhibitory monomeric forms of phospholamban in mouse heart impairs cardiac contractility. J. Biol. Chem. 275, 14985–14991 (2000)

  41. 41

    Allred, A. J., Chappell, M. C., Ferrario, C. M. & Diz, D. I. Differential actions of renal ischemic injury on the intrarenal angiotensin system. Am. J. Physiol. Renal 279, F636–F645 (2000)

  42. 42

    Chappell, M. C., Milsted, A., Diz, D. I., Brosnihan, K. B. & Ferrario, C. M. Evidence for an intrinsic angiotensin system in the canine pancreas. J. Hypertens. 9, 751–759 (1991)

Download references


We thank D. Ganten for supplying us with tissue from SHRSP rats. Eve and Tin antibodies were a gift from M. Frasch. We acknowledge the Samuel Lunenfeld Research Institute's CMHD Mouse Physiology Facility for their technical screening services. This study was supported by Amgen and by grants from the Israel Science Foundation and the German–Israeli Foundation for Scientific Research and Development to C.Y. and Y.Y. J.M.P. holds a Canadian Research Chair in Cell Biology. M.A.C. is supported in part by a Canadian Institutes of Health Research fellowship.

Author information

Author notes

  1. Renu Sarao and Gavin Y. Oudit: These authors contributed equally to the work


  1. Amgen Research Institute/Ontario Cancer Institute, University of Toronto, University Avenue, Toronto, Ontario, M5G 2M9, Canada

    • Michael A. Crackower
    • , Renu Sarao
    • , Ivona Kozieradzki
    • , Antonio J. Oliveira-dos-Santos
    • , Joan da Costa
    • , Liyong Zhang
    •  & Josef M. Penninger
  2. Departments of Medical Biophysics and Immunology, University of Toronto, University Avenue, Toronto, Ontario, M5G 2M9, Canada

    • Michael A. Crackower
    • , Liyong Zhang
    •  & Josef M. Penninger
  3. The Heart & Stroke/Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, University Avenue, Toronto, Ontario, M5G 2M9, Canada

    • Michael A. Crackower
    • , Gavin Y. Oudit
    • , Liyong Zhang
    • , Peter H. Backx
    •  & Josef M. Penninger
  4. Department of Physiology, University of Toronto, University Avenue, Toronto, Ontario, M5G 2M9, Canada

    • Gavin Y. Oudit
    •  & Peter H. Backx
  5. Department of Medicine and the University Health Network, University of Toronto, University Avenue, Toronto, Ontario, M5G 2M9, Canada

    • Gavin Y. Oudit
    • , York Pei
    • , James Scholey
    • , Peter H. Backx
    •  & Yoram Yagil
  6. Division of Cellular & Molecular Biology, University Health Network, Ontario Cancer Institute, University of Toronto, University Avenue, Ontario, M5G 2M9, Toronto, Canada

    • Sam E. Scanga
    •  & Armen S. Manoukian
  7. IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr Bohr Gasse, A-1030, Vienna, Austria

    • Renu Sarao
    • , Ivona Kozieradzki
    • , Liyong Zhang
    •  & Josef M. Penninger
  8. Laboratory for Molecular Medicine, Department of Nephrology and Hypertension, Faculty of Health Science, Ben-Gurion University Barzilai Medical Center Campus, 78306, Ashkelon, Israel

    • Chana Yagil
  9. The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, 27157-1032, USA

    • Carlos M. Ferrario
    •  & Mark C. Chappell


  1. Search for Michael A. Crackower in:

  2. Search for Renu Sarao in:

  3. Search for Gavin Y. Oudit in:

  4. Search for Chana Yagil in:

  5. Search for Ivona Kozieradzki in:

  6. Search for Sam E. Scanga in:

  7. Search for Antonio J. Oliveira-dos-Santos in:

  8. Search for Joan da Costa in:

  9. Search for Liyong Zhang in:

  10. Search for York Pei in:

  11. Search for James Scholey in:

  12. Search for Carlos M. Ferrario in:

  13. Search for Armen S. Manoukian in:

  14. Search for Mark C. Chappell in:

  15. Search for Peter H. Backx in:

  16. Search for Yoram Yagil in:

  17. Search for Josef M. Penninger in:

Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Josef M. Penninger.

Supplementary information

About this article

Publication history



Issue Date


Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.