Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block.
Previous studies have suggested that angiotensin II (Ang II) modulates cardiac contractility, rhythm, metabolism, and structure. However, it is unclear whether the cardiac effects are due to direct actions of Ang II on the myocardium or if they are due to secondary effects mediated through the hemodynamic actions of Ang II. In this study, we used the alpha-myosin heavy chain (alphaMHC) promoter to generate transgenic mice overexpressing angiotensin II type 1 (AT1a) receptor selectively in cardiac myocytes. The specificity of transgene expression in the transgenic offspring was confirmed by radioligand binding studies and reverse transcription-PCR. The offspring displayed massive atrial enlargement with myocyte hyperplasia at birth, developed significant bradycardia with heart block, and died within the first weeks after birth. Thus, direct activation of AT1 receptor signaling in cardiac myocytes in vivo is sufficient to induce cardiac myocyte growth and alter electrical conduction.
Hein
L
L
Falk Cardiovascular Research Center and Department of Medicine, 300 Pasteur Drive, Stanford University School of Medicine, Stanford, CA 94305, USA.
Stevens
M E
ME
Barsh
G S
GS
Pratt
R E
RE
Kobilka
B K
BK
Dzau
V J
VJ
D000818:Animals; D001835:Body Weight; D002216:Captopril / Q000494:pharmacology; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology; D004562:Electrocardiography; D006321:Heart / Q000033:anatomy & histology / Q000502:physiology*; D006327:Heart Block; D006339:Heart Rate; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D009929:Organ Size; D016133:Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012016:Reference Values
D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D011993:Recombinant Fusion Proteins; D002216:Captopril; D018995:Myosin Heavy Chains