Mecanismos envolvidos no efeito cardioprotetor daAng-(1-7) em ratos submetidos ao modelo de hipertensãoDOCA-Sal

Abstract

Recently there has been growing evidence suggesting that beneficial effects of angiotensin-(1-7) in the heart are mediated by its receptor Mas. However, the signaling pathways involved in these effects in cardiomyocytes are unknown. The aim of our study was to evaluate the mechanism underlying the protective effect of Ang (1-7) in rats subjected to 6 weeks of DOCA-salt treatment. At first in this study we evaluated the cardiovascular and cellular responses in Sprague Dawley (SD) and transgenic rats that overexpress Ang-(1-7) in the testis (TG) subjected to DOCA-salt model. SD DOCA rats, showed an increase in SBP compared to their controls, however TG DOCA rats presented less pronounced increase in SBP. Echocardiography studies showed that TG DOCA animals present reduced cardiac hypertrophy, when compared to SD DOCA rats. These results were confirmed by real time PCR studies showing the upregulation of cardiac stress markers (ANF and -MHC) in SD DOCA rats, but not in TG DOCA rats. By echocardiography we also observed that SD DOCA rats present a hyperdynamic heart, yet they are in the offset phase of the disease. However, our results indicate that at the cellular level the progression of the disease is occurring, due to the Ca2+ signaling dysfunction observed in cardiac cells from SD DOCA hearts. Interestingly, all these parameters were not altered in TG DOCA rats. Taken together, our data shows that overexpression of Ang-(1-7) in TG rats protects these animals against DOCA-salt pathological remodeling, however a question remains whether the Ang-(1-7) cardioprotective effects were due to the reduced BP in TG DOCA rats. In order to answer this question were developed two groups of DOCA-salt treated rats that with BP maintained at levels similar to TG DOCA rats. SD controlled arterial blood pressure (CABP) rats that received a lower dose of DOCA than TG DOCA rats, and SD hydralazine treated rats. SD HYDRALAZINE group received the same dose of DOCA as TG DOCA rats, in addition to hydralazine. Our results showed that animals that received a lower dose of DOCA (SD CABP) showed fewer changes in all parameters evaluated by echocardiography (hypertrophy and cardiac function), and by confocalstudies, when compared to TG DOCA rats. In contrast, rats from Hydralazine treated group present a pattern of responses quiet similar to SD DOCA group, suggesting that the mineralocorticoid is the mainly responsible for cardiovascular changes the observed in the DOCA-salt model. Therefore, we can conclude from the results obtained in this study that overexpression of Ang-(1-7) in transgenic rats subjected to the DOCA-salt model exerts besides a pressor effect, a local effect in the heart at various stages of pathologic remodeling.