ABSTRACT
OBJECTIVE: It has been shown that Ang-(1-7) has cardioprotective actions. To directly investigate the effects of Ang-(1-7) specifically in the heart, we generated and characterized transgenic (TG) rats which express an Ang-(1-7)-producing fusion protein driven by the alpha-MHC promoter. METHODS AND RESULTS: After microinjection of the transgene into fertilized rat zygotes, we obtained four different transgenic lines. Homozygous animals were analyzed with regard to the expression profile of the transgene by ribonuclease protection assay. Transgene expression was detected mainly in the heart with weak or no expression in other organs. Heterozygous TG(hA-1-7)L7301 rats presented a significant increase in cardiac Ang-(1-7) concentration compared with control rats (17.1+/-2.1 versus 3.9+/-1.4 pg/mg protein in SD rats). Radiotelemetry analysis revealed that TG rats presented no significant changes in blood pressure and heart rate compared with normal rats. Overexpression of Ang-(1-7) in the heart produced slight improvement in resting cardiac function (+ dT/dt: 81530+/-1305.0 versus 77470+/-345.5 g/s bpm in SD rats, p < 0.05), which was in keeping with the enhanced [Ca(2+)] handling observed in cardiomyocytes of TG rats. TG(hA-1-7)L7301 rats also showed a greater capacity to withstand stress since TG rats showed a less pronounced deposition of collagen type III and fibronectin induced by isoproterenol treatment in the subendocardial area than in corresponding controls. In addition, hearts from TG rats showed reduced incidence and duration of reperfusion arrhythmias in comparison with SD rats. CONCLUSION: These results indicate that Ang-(1-7) has blood pressure-independent, antifibrotic effects, acting directly in the heart.
Subject(s)
Angiotensin I/metabolism , Gene Expression Regulation , Heart Ventricles/pathology , Peptide Fragments/metabolism , Angiotensin I/genetics , Animals , Arrhythmias, Cardiac/physiopathology , Blood Pressure/physiology , Calcium/metabolism , Disease Models, Animal , Fibrosis , Heart Rate/physiology , Isoproterenol/toxicity , Male , Myocardial Reperfusion Injury/physiopathology , Myocytes, Cardiac/metabolism , Myosin Heavy Chains/genetics , Myosin Heavy Chains/metabolism , Peptide Fragments/genetics , Promoter Regions, Genetic , Rats , Rats, Sprague-Dawley , Rats, Transgenic , Telemetry/methodsABSTRACT
O sistema renina-angiotensina (SRA) é considerado, um dos mais importantes sistemas reguladores para a homeostase cardiovascular. A influência desse sistema sobre as funções cardiovasculares e renais é extremamenteampla e complexa, envolvendo múltiplos mediadores, receptores e mecanismos de sinalização intracelular variados. Nesta breve revisão, serão abordados os múltiplos efeitos cardiovasculares e renais do SRA, com ênfase na angiotensina II (Ang II), o efetor hemodinâmico dominante desse sistema.