Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice.
The angiotensin II type 2 (AT2) receptor is upregulated in the left ventricle in heart failure, but its pathophysiological roles in vivo are not understood. In the present study, AT2 receptors were expressed in transgenic (TG) mice using the ventricular-specific myosin light-chain (MLC-2v) promoter. In TG compared with nontransgenic (NTG) mice, in vivo left ventricular (LV) systolic pressure and peak +dP/dt were depressed while LV diastolic pressure was elevated (P < 0.05). Echocardiography showed severely depressed LV fractional shortening, increased systolic and diastolic dimensions, and wall thinning (P < 0.05). Confocal and electron microscopy studies revealed an increase in the size of myocytes and interstitial spaces as well as an increase in interstitial collagen, disruption of the Z-band, and changes in cytochrome c localization. The changes were most prominent in the highest-expressing TG line, which implies a dose-response relationship. AT2 overexpression was also directly associated with the increase of phosphorylated protein levels of PKC-alpha, PKC-beta, and p70S6 kinase. These data demonstrate that ventricular myocyte-specific expression of AT2 receptors promotes the development of dilated cardiomyopathy and heart failure in vivo.
Yan
Xinhua
X
Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, 185 Pilgrim Road, Boston, MA 02215, USA.
Price
Robert L
RL
Nakayama
Masaharu
M
Ito
Kenta
K
Schuldt
Adam J T
AJ
Manning
Warren J
WJ
Sanbe
Atsushi
A
Borg
Thomas K
TK
Robbins
Jeffrey
J
Lorell
Beverly H
BH
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D032383:Myocytes, Cardiac / Q000473:pathology / Q000648:ultrastructure; D018994:Myosin Light Chains / Q000235:genetics; D011401:Promoter Regions, Genetic; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D016276:Ventricular Function; D016277:Ventricular Function, Left
D018994:Myosin Light Chains; D044139:Receptor, Angiotensin, Type 2