Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death.
To investigate the local effects of angiotensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the alpha-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death.
Xiao
Hong D
HD
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
Fuchs
Sebastien
S
Campbell
Duncan J
DJ
Lewis
William
W
Dudley
Samuel C
SC
Kasi
Vijaykumar S
VS
Hoit
Brian D
BD
Keshelava
George
G
Zhao
Hui
H
Capecchi
Mario R
MR
Bernstein
Kenneth E
KE
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology*; D001281:Atrial Fibrillation / Q000473:pathology*; D001794:Blood Pressure; D001920:Bradykinin / Q000378:metabolism; D003645:Death, Sudden / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D006327:Heart Block / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018995:Myosin Heavy Chains / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D014018:Tissue Distribution
D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D018995:Myosin Heavy Chains; D001920:Bradykinin