Avaliação bioquímica e ecodopplercardiográfica de camundongos Mas-KO submetidos à coarctação da aorta torácica

Abstract

The heptapeptide angiotensin –(1-7) (Ang – (1-7)) exerts its effects through interaction with Mas receptor. As a result of this interaction, an essential contra regulatory role of Ang – (1-7) against the constrictor and remodeling effects of the renin angiotensin system (RAS), represented by angiotensin II (Ang II)/AT1 receptor axis is achieved. Hyperactivity of RAS is a well-known determinant in physiopathology of cardiovascular diseases, leading to increased blood pressure and remodeling of the heart and vessels. Besides it stimulates inflammatory pathways everywhere in the organism. In this study, we evaluated the role of Mas receptor on cardiac remodeling in a pressure overload model induced by thoracic aortic constriction (TAC) in Mas-KO mice. TAC was induced in the transverse aorta, between innominate and left carotid arteries. The occlusion was considered mild, occupying approximately 40% of aortic lumen. Echocardiographic evaluation was performed before (time 0), 7 days (time 1) and 30 days (time 2) after TAC procedure. Conventional echocardiographic analysis and deformation analysis using Speckle Tracking echocardiography were accomplished offline. The mice were euthanized and their hearts excised. Fragments of the left ventricle (LV) were used for biochemical analysis of mRNA gene expression related to cardiac dysfunction and remodeling. The echocardiographic data of control showed clearly the systolic dysfunction developed by Mas-KO mice. Low fractional shortening (FS) (24,36 ± 3,53 versus 39,44 ± 3,26%, P<0,0001), ejection fraction (EF) (49,00 ± 5,94 versus 70.57 ± 4,12%, P<0,0001), cardiac output (14,03 ± 2,35 versus 18,01 ± 3,63 ul/min, P<0,0001) and systolic volume (30,11 ± 4,54 versus 42,33 ± 6,85 ul, P<0,0001), besides left ventricular chamber and walls morphological adaptations when compared to WT mice. Conventional echocardiographic data did not show any changing in WT mice 30 days after the mild TAC, but Mas-KO mice had a compensatory changing in heart function observed as increasing of FS (29,85 ± 5,53 versus 38,34 ± 4,19%, P<0,01) and EF (57,42 ± 8,35 versus 68,91 ± 5,49%, P<0,01) along with morphological changings. There were not many significant alterations in the deformation analysis in the control time, but it could be seen already that Mas-KO depicts asynchrony of endocardial longitudinal displacement and strain. Thirty days after TAC WT and Mas-KO mice developed a significant reduction of epicardial circumferential strain and strain rate values, what could mean that the first adaptations of heart mechanics to pressure overload in the model applied occurs in this component. There was an increasing asynchrony activity between walls after TAC in both animals, that was further worsened in Mas-KO mice. It was observed important asynchrony in endocardial and epicardial longitudinal displacement, epicardial longitudinal strain and strain rate, along with short axis epicardial radial displacement. Unexpectedly biochemical analysis of mRNA showed increased expression of ANP, BNP and MHCB only in WT mice, although evaluation of LV relative wall thickness and LV myocardial index mass demonstrated that both had tendency to concentric hypertrophy development. Collagen III and TGFß mRNA increased in WT and Mas-KO mice. The results indicate that the Mas-KO mice are more sensitive in developing functional adaptation when submitted to a model of mild pressure overload, observed through echocardiographic evaluation as increased FS and EF and morphological modifications, although some biochemical results to support these changes were unexpected.