Santos Robson A S, Ferreira Anderson J, Nadu Ana Paula, Braga Aline N G, de Almeida Alvair Pinto, Campagnole-Santos Maria José, Baltatu Ovidiu, Iliescu Radu, Reudelhuber Timothy L, Bader Michael
Laboratory of Hypertension, Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901 Brazil.
Physiol Genomics. 2004 May 19;17(3):292-9. doi: 10.1152/physiolgenomics.00227.2003.
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).
血管紧张素 -（1 - 7）[ANG -（1 - 7）]是肾素 - 血管紧张素系统中最近被描述的一种七肽产物。由于在接受心脏保护药物治疗的动物中ANG -（1 - 7）的生物合成增加，并且血管紧张素转换酶2（一种参与ANG -（1 - 7）生物合成的酶）基因的失活会导致心脏功能障碍的发生，因此有人提出ANG -（1 - 7）具有心脏保护特性。为了直接验证这种可能性，我们利用一种新型融合蛋白方法培育出了长期过量产生ANG -（1 - 7）的转基因大鼠。TGR（A1 - 7）3292大鼠表现出巨细胞病毒启动子驱动的转基因在睾丸特异性表达，与非转基因对照大鼠相比，循环中的ANG -（1 - 7）增加了一倍。放射性遥测血流动力学测量显示，转基因大鼠的每日和夜间心率有小幅但显著的增加，并且通过dP/dt测量估计的每日和夜间心脏收缩力有轻微但显著的增加。令人惊讶的是，TGR（A1 - 7）3292大鼠比对照动物对异丙肾上腺素诱导的心脏肥大具有显著更高的抵抗力。此外，转基因大鼠在离体Langendorff心脏标本中显示出再灌注心律失常持续时间缩短和缺血后功能改善。这些结果支持循环ANG -（1 - 7）具有心脏保护作用，并为评估ANG -（1 - 7）的功能作用提供了一种新工具。
