Impairment of in vitro and in vivo heart function in angiotensin-(1-7) receptor MAS knockout mice.
In this study we investigated the effects of the genetic deletion of the angiotensin (Ang)-(1-7) receptor Mas on heart function. Localization of Mas in the mouse heart was evaluated by binding of rhodamine-labeled Ang-(1-7). Cardiac function was examined using isolated heart preparations. Echocardiography was used to confirm the results obtained with isolated heart studies. To elucidate the possible mechanisms involved in the cardiac phenotype observed in Mas(-/-) mice, whole-cell calcium currents in cardiomyocytes and the expression of collagen types I, III, and VI and fibronectin were analyzed. Ang-(1-7) binding showed that Mas is localized in cardiomyocytes of the mouse heart. Isolated heart techniques revealed that Mas-deficient mice present a lower systolic tension (average: 1.4+/-0.09 versus 2.1+/-0.03 g in Mas(+/+) mice), +/-dT/dt, and heart rate. A significantly higher coronary vessel resistance was also observed in Mas-deficient mice. Echocardiography revealed that hearts of Mas-deficient mice showed a significantly decreased fractional shortening, posterior wall thickness in systole and left ventricle end-diastolic dimension, and a higher left ventricle end-systolic dimension. A markedly lower global ventricular function, as defined by a higher myocardial performance index, was observed. A higher delayed time to the peak of calcium current was also observed. The changes in cardiac function could be partially explained by a marked change in collagen expression to a profibrotic profile in Mas-deficient mice. These results indicate that Ang-(1-7)-Mas axis plays a key role in the maintenance of the structure and function of the heart.
Santos
Robson A S
RA
Department of Physiology and Biophysics, Biological Sciences Institute, Belo Horizonte, MG, Brazil. marrob@ciclope.Lcc.ufmg.br
Castro
Carlos H
CH
Gava
Elisandra
E
Pinheiro
Sérgio V B
SV
Almeida
Alvair P
AP
Paula
Renata Dutra de
RD
Cruz
Jader S
JS
Ramos
Anderson S
AS
Rosa
Kaleizu T
KT
Irigoyen
Maria C
MC
Bader
Michael
M
Alenina
Natalia
N
Kitten
Gregory T
GT
Ferreira
Anderson J
AJ
D000803:Angiotensin I / Q000378:metabolism; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003331:Coronary Vessels / Q000503:physiopathology; D004452:Echocardiography; D004594:Electrophysiology; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000378:metabolism; D013599:Systole; D014655:Vascular Resistance; D016276:Ventricular Function
D015220:Calcium Channels; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D003094:Collagen; D000803:Angiotensin I; C118790:angiotensin I (1-7)