Hemodynamic phenotyping of transgenic rats with ubiquitous expression of an angiotensin-(1-7)-producing fusion protein

Abstract

Activation of the angiotensin (Ang) converting enzyme 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system 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 were similar to control SD rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure, assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma ANP and higher urinary sodium concentration. 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 decreased total peripheral resistance. TG7371 rats also presented increased cardiac and global sympathetic tone, increased plasma 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 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.

Clinical efficacy of sacubitril-valsartan combined with acute ST-segment elevation myocardial infarction after reperfusion: A systematic review and meta-analysis

“…After entering the blood, renin catalyzes angiotensin I in the blood and converts angiotensin I into angiotensin II under the action of angiotensin converting enzyme ( 63 ). The main function of angiotensin II is to increase blood pressure by tightening blood vessels and stimulating the adrenal gland to secrete aldosterone, thereby further increasing the reabsorption of sodium ions and the secretion of potassium ions in human blood ( 64 ). If the secretion of angiotensin II is abnormal, it will cause oxidative stress and inflammatory reaction, which has important significance in the progression of atherosclerosis and cardiovascular disease ( 65 ).…”

Countering the classical renin–angiotensin system

“…In the recent study published in Clinical Science, Alves et al [14] have engineered a new hypotensive transgenic rat model (TG7371) whose tissues overexpress the mRNA of an Ang-(1-7)-producing fusion protein using human glial fibrillary acidic protein (hGFAP) promoter, signal peptide from human renin, immunoglobulin fragment from mouse IgG2b, a furin cleavage site preceding the mRNA for Ang-(1-7) followed by a stop codon, to counter-regulate the ACE/Ang II/AT 1 R axis, circumventing current limitations to the therapeutic administration of Ang-(1-7), similar to previous methodology [19,20]. The authors compared the TG7371 rats to wild-type Sprague-Dawley (SD) rats, reporting that TG7371 rats have decreased total peripheral resistance (TPR), increased plasma atrial natriuretic peptide (ANP), and lower blood pressure, compared with SD rats.…”

“…Multiple questions arise from the findings and the TG7371 transgenic rat model created by Alves et al [14], the first one being: is overexpression of Ang-(1-7) in the model indicating physiological function of the peptide, or is this an animal model of the effects of overexpression? Different explanations can be given to the observed hyperactivity of AVP and the SNS.…”

“…Additionally, a recent review showed that microinjection of both Ang-(1-7) and Ang II into the nucleus tractus solitarius (NTS), reduced blood pressure in urethane-anesthetized rats [13]. However, as noted in the recent study by Alves et al [14], there is considerable ambiguity regarding the Ang II-like versus the Ang II oppositional effects in the brain and kidneys, also discussed in a previous review by these authors [13].…”

Arterial Hypertension

“…Acting predominantly via the Mas1 receptor, Ang(1-7) induces vasodilation via nitric oxide (NO) production in endothelial cells, and downregulates inflammation, proliferation, and fibrosis in the cardiovascular system (52). Ang(1-9) is protective against cardiomyocyte death and reduces infarct size through Akt activation in an AT2R-dependent manner (53,54). It also reduced…”