Expression of an angiotensin-(1–7)-producing fusion protein produces cardioprotective effects in rats

Abstract

Angiotensin-(1-7) [ANG-(1-7)] is a recently described heptapeptide product of the renin-angiotensin system. Because biosynthesis of ANG-(1-7) increases in animals treated with cardioprotective drugs and inactivation of the gene for angiotensin converting enzyme 2 [an enzyme involved in the biosynthesis of ANG-(1-7)] leads to the development of cardiac dysfunction, it has been suggested that ANG-(1-7) has cardioprotective properties. To directly test this possibility, we have generated transgenic rats that chronically overproduce ANG-(1-7) by using a novel fusion protein methodology. TGR(A1-7)3292 rats show testicular-specific expression of a cytomegalovirus promoter-driven transgene, resulting in a doubling of circulating ANG-(1-7) compared with nontransgenic control rats. Radiotelemetry hemodynamic measurements showed that transgenic rats presented a small but significant increase in daily and nocturnal heart rate and a slight but significant increase in daily and nocturnal cardiac contractility estimated by dP/d t measurements. Strikingly, TGR(A1-7)3292 rats were significantly more resistant than control animals to induction of cardiac hypertrophy by isoproterenol. In addition, transgenic rats showed a reduced duration of reperfusion arrhythmias and an improved postischemic function in isolated Langendorff heart preparations. These results support a cardioprotective role for circulating ANG-(1-7) and provide a novel tool for evaluating the functional role of ANG-(1-7).

Effect of Angiotensin (1-7) on Heart Function in an Experimental Rat Model of Obesity

“…In contrast to the present study, Ferreira et al showed an improved cardiac function, indicated by elevated dp/dt anddp/dt and furthermore, an attenuation of the isoproterenolinduced cardiac fibrosis in transgenic rats. Previous studies also indicated an antifibrotic action of Ang(1-7) in vitro and in vivo (Santos et al, 2004;Ferreira et al, 2010;Dong et al, 2012;McCollum et al, 2012;Acuña et al, 2014). In contrast to these findings, the present study revealed no antifibrotic effect of Ang(1-7) in a transgenic rat model.…”

“…Thus, the findings of Ferreira et al seemed to be due to local production of cardiac Ang(1-7), whereas our results were rather caused by systemic alterations. Santos et al (2004) measured Ang(1-7) in the same model as we used, demonstrating elevated Ang(1-7) plasma concentration, but unaltered tissue levels, which may be a result of the short half-life of Ang(1-7), which is about 10 s (Yamada et al, 1998).…”

“…In their study Ferreira et al used a transgenic rat model, which expressed an Ang(1-7)-producing fusion protein, specifically in the heart, which resulted in a cardiac overexpression of Ang(1-7), whereas the plasma Ang(1-7) concentration remained unchanged (Ferreira et al, 2010). In contrast, our transgenic rat model was generated by an Ang(1-7)-producing fusion protein, expressed in testis, which led to an increase in circulating Ang(1-7) levels (Santos et al, 2004;Schuchard et al, 2015). Thus, the findings of Ferreira et al seemed to be due to local production of cardiac Ang(1-7), whereas our results were rather caused by systemic alterations.…”

“…This fusion protein is then cleaved in the testis tissue resulting in an about 4.5-fold increase in testicular Ang(1-7) and a 2.5-fold increase in circulating Ang(1-7) (Schuchard et al, 2015). In detail, the generation of these transgenic rats was described previously by Santos et al (2004).…”

Evidence for a functional cardiac interaction between losartan and angiotensin‐(1–7) receptors revealed by orthostatic tilting test in rats

“…Therefore, we could speculate that, part of this antiarrhythmogenic property of losartan could be mediated by an interaction with Ang-(1-7) receptors. This seems to be an interesting possibility, since cardioprotective effects were recently described for Ang-(1-7) (Santos et al, 2004). Clearly, future studies are necessary to unravel the mechanism and other consequences involved in the interaction between losartan and Ang-(1-7) receptors on the cardiac function.…”