Anxiolytic Effects of Overexpressing Angiotensin Converting Enzyme 2 (ACE2) in Female Mice

Abstract

Considerable evidence has implicated the renin‐angiotensin system (RAS) as an important target for the therapeutic alleviation of stress‐related mood disorders. Along these lines, the ‘pro‐stress’ actions of Angiotensin‐II are largely thought to be mediated by the angiotensin type‐1 receptor (AT1R). On the other hand, the protective limb of the RAS that depends on the conversion of angiotensin‐II to angiotensin‐(1–7) by angiotensin‐converting enzyme 2 (ACE2) has been postulated to dampen stress and relieve anxiety. We have previously found that augmenting ACE2 activity has potent anxiolytic and hypothalamic‐pituitary‐adrenal (HPA) axis‐dampening effects in male mice. Relative to males, females are more susceptible to stress‐related mood disorders; however, whether increasing ACE2 activity in females also blunts stress responses has not been determined. This study tests the hypothesis that ACE2 overexpression decreases anxiety‐like behavior and attenuates stress‐induced HPA axis activation in female mice. We used the Cre/Lox system to generate female mice that ubiquitously overexpress ACE2. Female ACE2 knock‐in (ACEKI) mice and their wild‐type littermate controls were tested in the elevated‐plus maze (EPM), Light‐Dark Box (LDB), and Graham Cracker Test to evaluate the impact that augmenting ACE2 expression has on anxiety‐like behavior. Female mice were also subjected to an acute 30 min restraint stress challenge and blood samples were collected in order to evaluate HPA (i.e., corticosterone) reactivity. As expected, Cre‐Lox mediated overexpression of ACE2 resulted in elevated ACE2 mRNA and enzymatic activity in all tissues examined (i.e., hypothalamus, pituitary, blood, and brain). Relative to controls, ACE2KI mice spent significantly (p < 0.05) more time in the open arms of the EPM and in the light side of the LDB. When placed in a novel environment, ACEKI mice exhibited a significantly (p<0.05) decreased latency to consume graham crackers relative to controls. Importantly, total distance traveled in the EPM was not different between the groups, indicating that the locomotor activity of the female mice is unchanged by ACE2 overexpression. Interestingly, basal and acute stress‐induced corticosterone levels did not differ between ACE2KI and WT female mice. These results suggest that although neuroendocrine response to acute restraint was unaffected in females, ACE2 overexpression has anxiolytic effects on both male and female ACE2KI mice. Furthermore, our findings support the idea that the RAS may be a worthy target in the search for novel therapeutic interventions for stress‐related disorders.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.