Abstract 407: Aminopeptidase A (APA)/Ang(2-10) and APA/AngIII are the Dominant Axes in the Metabolism of Angiotensin Peptides in Mice Plasma
ACE2 is considered an important enzyme in the degradation of Angiotensin (Ang) I (1-10) and especially of Ang II (1-8), as demonstrated by the rapid dissipation of this peptide when recombinant ACE2 is infused but the steady state level of ACE2 in plasma is low. We examined levels of multiple Ang peptides in plasma under steady state conditions in WT and ACE2KO mice on C57BL genetic background (n=4 and 5, respectively). Liquid chromatography mass-spectrometry-based approach which enables concurrent evaluation of ten different angiotensins at physiologic levels (pg/mL) was used for multiple peptide quantification.
The levels of angiotensin peptides in WT mice were highest for Ang I (1-10) (1295±313 pg/mL), Ang (2-10) (657±173 pg/mL) and Ang III (2-8) (1047±178 pg/mL). In contrast, plasma levels of Ang II (1-8), the main effector peptide of the RAS, and Ang (1-7), the product of cleavage of Ang II by ACE2, were very low (7.8±2 and 3.5±0 pg/mL, respectively). In ACE2 KO mice, Ang II and Ang (1-7) levels were not significantly different from WT. Activity of Aminopeptidase A, an enzyme that converts Ang (1-10) to Ang (2-10) and cleaves Ang II (1-8) to Ang III (2-8), was significantly increased in ACE2KO (n=11) as compared to WT (n=17) (149±11 vs. 94±9 RFU/ul/hr, respectively, p<0.001). This finding along with increased ratio of Ang (2-10)/Ang(1-8) (175±31 vs. 84±4, p<0.01, respectively) suggests increased formation of Ang (2-10) from Ang (1-10) in ACE2KO mice by APA over the formation of Ang II (1-8) from Ang (1-10).
These results show that plasma Ang II and Ang (1-7) levels in WT and ACE2KO mice are low relative to the high levels of Ang (2-10) and Ang III (2-8). ACE2 deficiency does not result in plasma Ang II accumulation or reduced Ang (1-7) levels and is associated with an increase in serum APA activity. We conclude that in mice plasma the APA/Ang(2-10) and APA/AngIII pathways, and not ACE2/Ang(1-7), are dominant in the metabolism of Ang I and Ang II under steady state conditions.
Author Disclosures: J. Wysocki: None. S.K. Haque: None. M. Ye: None. D. Batlle: None.
- © 2014 by American Heart Association, Inc.