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.
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Ang II binds the ATR1 receptor leading to release of TNFα and IL-6, which is associated with hypertension, diabetes, and heart disease-major comorbidities in severe COVID-19.
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From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [52]
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Self-citation
- 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
- Venue
- Nature
- Published
- 2002-06
- Volume
- 417
- Issue
- 6891
- Pages
- 822-828
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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 › Genetics › 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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