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1 Laboratory of Hypertension, Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901 Brazil
2 Max-Delbrück-Center for Molecular Medicine, Berlin-Buch 13125, Germany
3 Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, Quebec H2W 1R7, Canada
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).
engineered protein; renin-angiotensin system; heart hypertrophy
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