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Nature 417, 822-828 (20 June 2002) | doi:10.1038/nature00786; Received 6 March 2002; Accepted 8 April 2002

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

Michael A. Crackower1,2,3, Renu Sarao1,4,5, Gavin Y. Oudit3,5,6,7, Chana Yagil8, Ivona Kozieradzki1,4, Sam E. Scanga9, Antonio J. Oliveira-dos-Santos1, Joan da Costa1, Liyong Zhang1,2,3,4, York Pei7, James Scholey7, Carlos M. Ferrario10, Armen S. Manoukian9, Mark C. Chappell10, Peter H. Backx3,6,7, Yoram Yagil7 & Josef M. Penninger1,2,3,4

  1. Amgen Research Institute/Ontario Cancer Institute, University of Toronto, University Avenue, Toronto, Ontario M5G 2M9, Canada
  2. Departments of Medical Biophysics and Immunology, University of Toronto, University Avenue, Toronto, Ontario M5G 2M9, Canada
  3. The Heart & Stroke/Richard Lewar Centre for Excellence in Cardiovascular Research, University of Toronto, University Avenue, Toronto, Ontario M5G 2M9, Canada
  4. Department of Physiology, University of Toronto, University Avenue, Toronto, Ontario M5G 2M9, Canada
  5. Department of Medicine and the University Health Network, University of Toronto, University Avenue, Toronto, Ontario M5G 2M9, Canada
  6. Division of Cellular & Molecular Biology, University Health Network, Ontario Cancer Institute, University of Toronto, University Avenue, Toronto, Ontario M5G 2M9, Canada
  7. IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr Bohr Gasse, A-1030, Vienna, Austria
  8. Laboratory for Molecular Medicine, Department of Nephrology and Hypertension, Faculty of Health Science, Ben-Gurion University Barzilai Medical Center Campus, Ashkelon 78306, Israel
  9. The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1032, USA
  10. These authors contributed equally to the work

Correspondence to: Josef M. Penninger1,2,3,4 Correspondence and requests for materials should be addressed to J.M.P. (e-mail: Email: jpenning@uhnres.utoronto.ca).

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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.