Abstract 477: Human Ang-(1-12) and Hemodynamic and Cardiac biometrics in Rats Overexpressing Human Angiotensinogen

Abstract

It has been reported that insertion of the human angiotensinogen (AGT) gene in rats does not cause hypertension as rat renin has no hydrolytic activity on human AGT. Initial studies in transgenic rats expressing the human AGT gene [TGR(hAGT)L1623] demonstrated the presence of human angiotensin-(1-12) [Ang-(1-12)] immunoreactivity in the heart of these rats. The exciting possibility that [TGR(hAGT)L1623] rats have increased precursor availability for Ang II formation from both human and rat origin stimulated further investigation of this model through measurements of arterial pressure and heart rate with implanted telemetry probes (Data Science International, MN), assessment of cardiac structure and function by echocardiography (VevoLAZR; VisualSonics Inc., Canada), and heart weight (n=9). Comparative studies were done in Sprague Dawley rats (SD; n=11). 24 h mean arterial pressures (Figure), but not heart rates, were significantly higher in [TGR(hAGT)L1623] rats compared to SD controls during 4 weeks of continuous measurement (starting at 13 weeks of age). Although there was no difference in systolic or diastolic function between these two strains, [TGR(hAGT)L1623] rats showed increased thickness of left ventricular posterior wall (2.3 ± 0.1 vs. 2.1 ± 0.1 mm; p<0.05) and diameter (8.1 ± 0.2 vs. 7.5 ± 0.1 mm; p<0.05) that was associated with increased heart weight (1.51 ± 0.03 vs 1.16 ± 0.01 g; p<0.001) and heart weight/tibia length ratio (34.6 ± 0.7 vs 28.6 ± 0.4 mg/mm; p<0.001). Detection of hypertension and cardiac Ang-(1-12) in rats with overexpression of the human AGT gene suggests a non-renin dependent enzymatic mechanism able to cleave Ang-(1-12) from the human substrate.