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Stress Dampening and Anxiolytic Effects of Overexpressing Angiotensin Converting Enzyme 2 in Female Mice
Author(s) -
Cahill Karlena M.,
Alleyne Amy R.,
Smeltzer Michael D.,
Raizada Mohan K.,
Kloet Annette D.,
Krause Eric G.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.737.7
Subject(s) - anxiolytic , elevated plus maze , endocrinology , medicine , renin–angiotensin system , angiotensin converting enzyme 2 , angiotensin ii , receptor , angiotensin converting enzyme , open field , anxiety , blood pressure , psychiatry , disease , covid-19 , infectious disease (medical specialty)
Accumulating evidence has revealed intricate roles for a number of components of the renin‐angiotensin system (RAS) in the progression or alleviation of stress‐related 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, a counter regulatory 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 exert stress‐dampening actions. We have previously found that stimulating this enzyme has potent anxiolytic and hypothalamic‐pituitary‐adrenal (HPA) axis dampening effects in male mice; however, the impact of stimulating this counter regulatory limb on stress‐related responses in females is yet to be explored. That being said, females are often considered to be more susceptible to stress‐related mood disorders, making it essential that novel therapeutic options for females are also uncovered. Therefore, in this set of studies, we tested the hypothesis that ACE2 has anxiolytic and endocrine stress‐dampening effects 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) and open field maze (OFM) to evaluate the impact of the genetic manipulation on anxiety‐like behavior. Mice were then subjected to an acute 30 min restraint stress challenge and blood samples were collected for the evaluation of HPA axis reactivity. As expected, overexpression of ACE2 leads to elevated ACE2 expression and activity in all tissues examined (i.e., hypothalamus, pituitary, blood, and brain). In regards to anxiety‐like behavior, a statistically significant increase (p < 0.05) in time spent in the open arms was observed in the ACE2KI mice relative to controls, demonstrating an anxiolytic effect of ACE2 overexpression. Total distance traveled in the EPM and OFM were not different between the groups, indicating that the locomotor activity of the female mice is unchanged by ACE2 overexpression. Finally, ACE2KI female mice also exhibited significantly reduced HPA axis activity relative to their wild‐type littermate counterparts (p < 0.05). Collectively, the results indicate that augmenting ACE2 activity reduces stress reactivity and anxiety‐like behavior in female mice. Support or Funding Information NIH:HL125805 and AHA GRNT33660969 (AdK), NIH: HL122494 (EGK), NIH HL033610 and HL102033 (MKR). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .