Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy.
Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that increased myocardial AT1 receptor density causes cardiac hypertrophy apart from high blood pressure we developed a transgenic rat model which expresses the human AT1 receptor under the control of the alpha-myosin heavy-chain promoter specifically in the myocardium. Expression was identified and quantified by northern blot analysis and radioligand binding assays, demonstrating overexpression of angiotensin II receptors in the transgenic rats up to 46 times the amount seen in nontransgenic rats. Coupling of the human AT1 receptor to rat G proteins and signal transduction cascade was verified by sensitivity to GTP-gamma-S and increased sensitivity of intracellular Ca2+ [Ca2+]i to angiotensin II in fluo-3 loaded transgenic cardiomyocytes. Transgenic rats exhibited normal cardiac growth and function under baseline conditions. Pronounced hypertrophic growth and contractile responses to angiotensin II, however, were noted in transgenic rats challenged by volume and pressure overload. In summary, we generated a new transgenic rat model that exhibits an upregulated myocardial AT1 receptor density and demonstrates augmented cardiac hypertrophy and contractile response to angiotensin II after volume and pressure overload, but not under baseline conditions.
Hoffmann
S
S
Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany. sigrid.hoffmann@zmf.ma.uni-heidelberg.de
Krause
T
T
van Geel
P P
PP
Willenbrock
R
R
Pagel
I
I
Pinto
Y M
YM
Buikema
H
H
van Gilst
W H
WH
Lindschau
C
C
Paul
M
M
Inagami
T
T
Ganten
D
D
Urata
H
H
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008566:Membranes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics*; D013997:Time Factors; D019076:Transgenes / Q000235:genetics
D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D002118:Calcium