Abstract P629: Effect of Circulating ACE2 Activity on plasma Angiotensin Peptides
Circulating ACE2, an enzyme that degrades Ang II, has been reported to be increased in rodent models of diabetes. Upregulation of ACE2 by increasing hydrolysis of Ang II could help downregulate RAS overactivity in a compensatory way and/or reflect increased Ang II metabolism. ACE2 activity in plasma, however, is relatively low even in diabetic conditions. Therefore, further increases in ACE2 effected by exogenous ACE2 administration could have a therapeutic action as a result of enhanced Ang II degradation and formation of Ang 1-7.
We examined the effect of a massive increase in circulating ACE2 activity on plasma levels of Ang II and other Ang peptides in mice rendered diabetic by STZ. Circulating ACE2 was amplified using ACE2 mini-circle (ACE2MC) gene delivery. Multiple Ang peptides were evaluated in plasma from STZ-mice that received ACE2MC and sham STZ-mice (n=6/group).
Plasma Ang II in STZ-ACE2MC mice were markedly lower than in STZ sham mice (3±1 vs. 22±13, pg/mL, respectively), but the difference was not significant owing to high variability. Since the seemingly lower Ang II levels could be influenced by either lower levels of the precursor peptide Ang I, increased degradation of Ang II, or both, a ratio between Ang II and Ang I was calculated. Ang II/Ang I ratio was significantly lower in STZ-ACE2MC as compared to STZ sham mice (0.15±0.05 vs. 0.35±0.06, p<0.05) indicating that per given amount of Ang I, there is significantly less Ang II in STZ-ACE2MC mice. This is consistent with enhanced Ang II degradation. Plasma levels of Ang 1-7 and Ang 1-9, the direct products of ACE2 cleavage of Ang I and Ang II, respectively, were very low and mostly below the level of detection. In plasma, Ang 1-7 is quickly converted to Ang 1-5, by ACE. Therefore, as an index of Ang II conversion to Ang 1-7, and as a surrogate for this conversion, we used Ang 1-5/Ang II ratio. This ratio was markedly higher in STZ-ACE2MC than in sham STZ-mice (3.15±1.5 vs. 0.38±0.07, p<0.05, respectively) suggesting an increased conversion of Ang II to Ang 1-7, and later to Ang 1-5 as a result of plasma ACE2 overexpression.
We conclude that a massive increase in circulating ACE2 is associated with an accelerated metabolism of Ang II. The increase in Ang II degradation seems best reflected by an increase in Ang 1-5/Ang II ratio.
Author Disclosures: J. Wysocki: None. M. Ye: None. A.M. Khattab: None. P.D. Serfozo: None. M. Osborn: None. D. Batlle: None.
- © 2015 by American Heart Association, Inc.