Cited by 1,733Renin-Angiotensin System StudiesEicosanoids and Hypertension PharmacologyCoagulation, Bradykinin, Polyphosphates, and Angioedema

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

Crackower, Michael A., Sarao, Renu, Oudit, Gavin Y., Yagil, Chana, Kozieradzki, Ivona, Scanga, Sam E., Oliveira-dos-Santos, Antonio J., da Costa, Joan, Zhang, Liyong, Pei, York, Scholey, James, Ferrario, Carlos M., Manoukian, Armen S., Chappell, Mark C., Backx, Peter H., Yagil, Yoram, Penninger, Josef M.·2002·Nature

DOI 10.1038/nature00786

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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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Authors: Crackower, M. A., Sarao, R., Oudit, G. Y., Yagil, C., Kozieradzki, I., Scanga, S. E., Oliveira-dos-Santos, A. J., da Costa, J., Zhang, L., Pei, Y., Scholey, J., Ferrario, C. M., Manoukian, A. S., Chappell, M. C., Backx, P. H., Yagil, Y., & Penninger, J. M.
Affiliations: University of Toronto (CA)
Institute of Molecular Biotechnology (AT)
University Health Network (CA)
Barzilai Medical Center (IL)
Atrium Health Wake Forest Baptist (US)
Corresponding author: Penninger, Josef M.
ORCID: Crackower, Michael A.
Oudit, Gavin Y.
Kozieradzki, Ivona
Zhang, Liyong
Pei, York
Scholey, James
Ferrario, Carlos M.
Chappell, Mark C.
Backx, Peter H.
Yagil, Yoram
Penninger, Josef M.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2002-06
Volume: 417
Issue: 6891
Pages: 822-828
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature00786
OpenAlex: W2025672718
Cited by: 1,733
References: 44
Citations by year: 2026: 12 · 2025: 25 · 2024: 38 · 2023: 88 · 2022: 117 · 2021: 215 · 2020: 311 · 2019: 38 · 2018: 22 · 2017: 33 · 2016: 42 · 2015: 38 · 2014: 53 · 2013: 54 · 2012: 60
FWCI: 38.64
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Amgen
German-Israeli Foundation for Scientific Research and Development
Canada Research Chairs
Israel Science Foundation
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Health Sciences › Medicine › Hematology › Coagulation, Bradykinin, Polyphosphates, and Angioedema
Keywords: angiotensin-converting enzyme 2, ACE2, cardiac function, hypertension, quantitative trait loci, X chromosome, cardiac contractility, angiotensin II, hypoxia, Acer, cardiac morphogenesis, rat model, mouse knockout
MeSH terms: Angiotensin II, Animals, Hypoxia, Blood Pressure, Cloning, Molecular, Drosophila melanogaster, Female, Heart, Hypertension, Peptidyl-Dipeptidase A, Male, Metalloendopeptidases, Myocardial Contraction, Myocardium, X Chromosome, Up-Regulation, Gene Expression Regulation, Enzymologic, Gene Deletion, Mice, Knockout, Quantitative Trait, Heritable, Radiation Hybrid Mapping, Drosophila Proteins, Mice, Rats

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

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