Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins.
Angiotensin converting enzyme related carboxypeptidase (ACE2) is a recently discovered homolog of angiotensin converting enzyme with tissue-restricted expression, including heart, and the capacity to cleave angiotensin peptides. We tested the hypothesis that cardiac ACE2 activity contributes to features of ventricular remodeling associated with the renin-angiotensin system by generating transgenic mice with increased cardiac ACE2 expression. These animals had a high incidence of sudden death that correlated with transgene expression levels. Detailed electrophysiology revealed severe, progressive conduction and rhythm disturbances with sustained ventricular tachycardia and terminal ventricular fibrillation. The gap junction proteins connexin40 and connexin43 were downregulated in the transgenic hearts, indicating that ACE2-mediated gap junction remodeling may account for the observed electrophysiologic disturbances. Spontaneous downregulation of the ACE2 transgene in surviving older animals correlated with restoration of nearly normal conduction, rhythm, and connexin expression.
Donoghue
Mary
M
Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
Wakimoto
Hiroko
H
Maguire
Colin T
CT
Acton
Susan
S
Hales
Paul
P
Stagliano
Nancy
N
Fairchild-Huntress
Victoria
V
Xu
Jian
J
Lorenz
John N
JN
Kadambi
Vivek
V
Berul
Charles I
CI
Breitbart
Roger E
RE
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001145:Arrhythmias, Cardiac; D002268:Carboxypeptidases / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism*; D003645:Death, Sudden; D015536:Down-Regulation; D004562:Electrocardiography; D004594:Electrophysiology; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D006327:Heart Block / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A; D017180:Tachycardia, Ventricular / Q000378:metabolism / Q000503:physiopathology*; D019076:Transgenes; D014693:Ventricular Fibrillation / Q000503:physiopathology; D000097003:Gap Junction alpha-5 Protein
D000085962:Angiotensin-Converting Enzyme 2; D002268:Carboxypeptidases; D018031:Connexin 43; D017630:Connexins; D007703:Peptidyl-Dipeptidase A; D000097003:Gap Junction alpha-5 Protein; C000705328:Ace2 protein, mouse