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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / blood
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Angiotensin II / metabolism
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Animals
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Blood Pressure / genetics
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Cloning, Molecular
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Drosophila Proteins*
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Drosophila melanogaster / enzymology
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Drosophila melanogaster / genetics
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Drosophila melanogaster / physiology
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Female
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Gene Deletion
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Gene Expression Regulation, Enzymologic
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Heart / physiology*
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Heart / physiopathology
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Hypertension / genetics
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Hypoxia / genetics
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Male
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Metalloendopeptidases / deficiency
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Metalloendopeptidases / genetics
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Metalloendopeptidases / metabolism
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Mice
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Mice, Knockout
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Myocardial Contraction
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Myocardium / enzymology*
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Peptidyl-Dipeptidase A / deficiency
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Peptidyl-Dipeptidase A / genetics
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Peptidyl-Dipeptidase A / metabolism*
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Quantitative Trait, Heritable
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Radiation Hybrid Mapping
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Rats
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Up-Regulation
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X Chromosome / genetics
Substances
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Drosophila Proteins
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Angiotensin II
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Acer protein, Drosophila
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Peptidyl-Dipeptidase A
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Metalloendopeptidases