Abstract 621: Chymase-mediated Angiotensin II Formation in the Heart of Rats Overexpressing the Human Angiotensinogen Gene
The creation of a transgenic rat model harboring the human angiotensinogen gene [TGR(hAGT)L1623] allows for the identification of alternate angiotensin II (Ang II) enzymatic pathways as rat renin has little, if any, hydrolytic activity on the human angiotensinogen protein. An initial study showing that hypertension associated with cardiac hypertrophy occurs in TGR(hAGT)L1623 rats led us to characterize the cardiac expression of renin angiotensin system components in 9 male TGR(hAGT)L1623 and 11 Sprague Dawley (SD) control rats. Cardiac Ang II content was higher in TGR(hAGT)L1623 rats when compared with SD rats (37±5 fmol/mg protein vs. 9.6±0.9 fmol/mg protein, respectively; P < 0.001). Although content of rat angiotensin-(1-12) [Ang-(1-12)] was comparable in both transgenic and control rats, chymase activity in the heart of both groups of rats was almost 9-fold higher when compared to cardiac angiotensin-converting enzyme (ACE) activity [chymase activity: 9.6±0.8 fmol/min/mg protein vs. 1.2±0.4 fmol/min/mg protein ACE activity in TGR(hAGT)L1623]. No significant differences in plasma renin concentration (PRC) was found between TGR(hAGT)L1623 and control SD rats (1.37±0.21 fmol/mL vs. 1.47±0.31 fmol/mL, respectively). Our findings further suggest that chymase enzyme (not ACE) is primarily responsible for generating Ang II in rat heart tissue. TGR(hAGT)L1623 rats represent a novel tool to investigate the direct contribution of renin-independent Ang II formation via chymase or other Ang II forming enzymes that expressed in the rat heart possess hydrolytic activity on human angiotensinogen.
Author Disclosures: S. Ahmad: None. J.L. VonCannon: None. M. Bader: None. J. Varagic: None. C.M. Ferrario: None.
- © 2014 by American Heart Association, Inc.