Angiotensin-converting enzyme 2 is an essential regulator of heart function

Abstract

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 options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Association of ACE2 and hypertension in the rat.
Figure 2: ACE2-deficient mice.
Figure 3: Loss of ACE2 results in severe contractile dysfunction.
Figure 4: Upregulation of hypoxia markers and increased angiotensin II levels in the absence of ACE2.
Figure 5: ACE/ACE2 double mutant mice do not develop cardiac dysfunction.
Figure 6: Expression of heart progenitor markers in Drosophila ACER mutant embryos.

References

  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)

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

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

    ADS  CAS  Article  Google Scholar 

  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)

    Google Scholar 

  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)

    CAS  Article  Google Scholar 

  8. 8

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

    ADS  CAS  Article  Google Scholar 

  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)

    CAS  PubMed  PubMed Central  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

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

    Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    ADS  CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  22. 22

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

    Google Scholar 

  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)

    Article  Google Scholar 

  24. 24

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

    CAS  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  26. 26

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

    ADS  CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  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)

    CAS  Google Scholar 

  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)

    CAS  Google Scholar 

  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)

    ADS  CAS  Article  Google Scholar 

  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)

    CAS  PubMed  PubMed Central  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  33. 33

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

    CAS  Article  Google Scholar 

  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)

    Article  Google Scholar 

  35. 35

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

    CAS  Article  Google Scholar 

  36. 36

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

    CAS  Article  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    ADS  CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

  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)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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

Affiliations

Authors

Corresponding author

Correspondence to Josef M. Penninger.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Crackower, M., Sarao, R., Oudit, G. et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417, 822–828 (2002). https://doi.org/10.1038/nature00786

Download citation

Further reading

Comments

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.