Funding outcome

Angiotensin converting enzyme 2 (ACE2) is becoming increasingly recognized as an important negative regulator of the renin-angiotensin system (RAS). Notably, chronic activation of the RAS is associated with diabetic cardiovascular disease. ACE2 degrades angiotensin II (AngII), a vasoconstrictive and pro-inflammatory peptide that has been shown to mediate cardiovascular damage. ACE2 degrades this peptide into Ang1-7, which has been shown to be cardioprotective. ACE2 is an X-linked gene that escapes X-linked inactivation and females may therefore harbour two active copies of the gene as opposed to males. It is possible that this plays a role in several sex differences noted between males and females in cardiovascular diseases. Specifically, women are more likely to receive a diagnosis of heart failure with preserved ejection fraction and less likely to respond to ACE inhibitors as treatment for cardiovascular diseases compared to males. We hypothesize that sex differences in diabetic cardiovascular disease are critically dependent on differences in ACE2 levels. This project will explore a global ACE2 knockout in a model of diabetic cardiovascular disease, and how this differentially impacts males and females. This work will be critical in determining how treatment outcomes differ between sexes. Furthermore, ACE2 is the receptor for cellular entry of COVID-19, which has been associated with cardiovascular damage and exhibits strong sex differences. Namely, males experience increased risk of severe infection and mortality. This project may contribute to understanding the mechanism underlying these sex differences by elucidating the effects of differential ACE2 expression.