Angiotensin-converting enzyme 2 is an essential regulator of heart function.
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.
Crackower
Michael A
MA
Amgen Research Institute/Ontario Cancer Institute and Department of Medical Biophysics and Immunology, University of Toronto, University Avenue, Toronto, Ontario M5G 2M9, Canada.
Sarao
Renu
R
Oudit
Gavin Y
GY
Yagil
Chana
C
Kozieradzki
Ivona
I
Scanga
Sam E
SE
Oliveira-dos-Santos
Antonio J
AJ
da Costa
Joan
J
Zhang
Liyong
L
Pei
York
Y
Scholey
James
J
Ferrario
Carlos M
CM
Manoukian
Armen S
AS
Chappell
Mark C
MC
Backx
Peter H
PH
Yagil
Yoram
Y
Penninger
Josef M
JM
D000804:Angiotensin II / Q000097:blood / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D003001:Cloning, Molecular; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics; D000860:Hypoxia / Q000235:genetics; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology*; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019655:Quantitative Trait, Heritable; D021101:Radiation Hybrid Mapping; D051381:Rats; D015854:Up-Regulation; D014960:X Chromosome / Q000235:genetics
D029721:Drosophila Proteins; D000804:Angiotensin II; C102762:Acer protein, Drosophila; D007703:Peptidyl-Dipeptidase A; D008666:Metalloendopeptidases