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, cerebrovas- cular disease, and stroke. Modulation of the renin-angio- tensin system, particularly inhibition of the angiotensin- converting enzyme (ACE), has become a prime strategy in the treatment of hypertension and heart failure. Re- cently the gene of a new ACE, termed ACE2, has been characterized. The ACE2 gene maps to defined quantita- tive 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 lev- els, 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 regu- late each other. The mechanisms and physiological sig- nificance of the interplay between ACE and ACE2 are not yet elucidated, but it may involve several new pep- tides 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 cardiovascu- lar diseases. Keywords Angiotensin-converting enzyme · Angiotensin-converting enzyme 2 · Knockout mice · Renin-angiotensin system Abbreviations ACE: Angiotensin converting-enzyme · RAS: Renin-angiotensin system · QTL: Quantitative trait locus U. Danilczyk · U. Eriksson · J. M. Penninger ( ✉ ) Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Toronto, Ontario, M5G 2C1, Canada e-mail: jpenning@uhnres.utoronto.ca Tel.: +1-416-2042241, Fax: +1-416-2042278 M. A. Crackower Department of Protein Sciences, Amgen Inc., Thousand Oaks, CA 91320, USA J. M. Penninger Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr Gasse 7, 1030 Vienna, Austria J Mol Med (2003) 81:227–234 DOI 10.1007/s00109-003-0419-x INVITED REVIEW Ursula Danilczyk · Urs Eriksson Michael A. Crackower · Josef M. Penninger A story of two ACEs Received: 13 November 2002 / Accepted: 27 December 2002 / Published online: 28 March 2003 © Springer-Verlag 2003 URSULA DANILCZYK received her Ph.D. in Immu- nology from the University of Toronto Graduate School in Toronto, Canada. She is pres- ently a Postdoctoral Fellow at the University Health Network in Toronto. Her research inter- ests include conditional gene expression in the heart. JOSEF MARTIN PENNINGER received his M.D. degree from the University of Innsbruck, Medical School, Austria. He is presently Full Professor in the Departments of Immunology and Medical Biophysics, Uni- versity of Toronto, Toronto, Canada, holds a Canada Re- search Chair in Cell Biology, and is the Scientific and Ad- ministrative Director of the In- stitute of Molecular Biotech- nology of the Austrian Acade- my of Sciences, Vienna, Aus- tria. His research focuses on the generation of genetically modified mice and animal models of human diseases, in- cluding cancer, cardiovascular disease, autoimmunity, and bone disease.