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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.

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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

Author notes

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

Affiliations

  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

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The authors declare that they have no competing financial interests.

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Correspondence to Josef M. Penninger.

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https://doi.org/10.1038/nature00786

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