Department of Physiology and Biophysics and INCT-Nanobiopharmaceutics, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Max-Delbrück Center for Molecular Medicine-MDC, Berlin, Germany.
Clin Sci (Lond). 2021 Sep 30;135(18):2197-2216. doi: 10.1042/CS20210599.
Activation of the angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system (RAS) induces protective mechanisms in different diseases. Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein. The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain. Plasma Ang-(1-7) levels, measured by radioimmunoassay (RIA) were similar to control Sprague-Dawley (SD) rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure (MAP), assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma atrial natriuretic peptide (ANP) and higher urinary sodium concentration. Moreover, evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decrease in total peripheral resistance (TPR). TG7371 rats, on the other hand, also presented increased cardiac and global sympathetic tone, increased plasma vasopressin (AVP) levels and decreased free water clearance. Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance. This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower blood pressure (BP). Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions.
肾素-血管紧张素系统（RAS）中的血管紧张素（Ang）-转换酶（ACE）2/Ang-（1-7）/MAS 受体途径的激活可在多种疾病中诱导保护机制。在此，我们描述了一种新的转基因大鼠品系（TG7371）的心血管表型，该品系表达一种产生 Ang-（1-7）的融合蛋白。转基因特异性 mRNA 和相应的蛋白质被证明存在于 TG7371 的所有评估组织中，在主动脉和大脑中的表达最高。通过放射免疫分析（RIA）测量的血浆 Ang-（1-7）水平与对照 Sprague-Dawley（SD）大鼠相似，但在下丘脑发现了高水平的 Ang-（1-7）。TG7371 的基础平均动脉压（MAP）较低，通过遥测或短期记录在清醒或麻醉大鼠中进行评估，与血浆心房利钠肽（ANP）升高和尿钠浓度升高相关。此外，用荧光微球评估局部血流和血液动力学参数显示不同组织（肾脏、肠系膜、肌肉、脾脏、棕色脂肪、心脏和皮肤）的血流显著增加，导致总外周阻力（TPR）降低。另一方面，TG7371 大鼠还表现出心脏和全身交感神经张力增加、血浆血管加压素（AVP）水平升高和游离水清除率降低。总之，我们的数据表明，表达一种产生 Ang-（1-7）的融合蛋白会由于广泛的血管扩张和外周阻力降低而导致低血压表型。这种表型与 ANP 增加以及 AVP 和交感神经驱动增加有关，这并没有完全补偿较低的血压（BP）。在这里，我们介绍了长期增加组织中表达的 Ang-（1-7）-融合蛋白对血液动力学的影响，并提供了一种新的工具来研究这种肽在不同病理生理条件下的作用。
