Pharmacologic Activation of Angiotensin-Converting Enzyme II Alleviates Diabetic Cardiomyopathy in db/db Mice by Reducing Reactive Oxidative Stress

Angiotensin-converting enzyme 2 (ACE2) is the main key for reducing angiotensin II (Ang II) in renin-angiotensin-aldosterone system (RAAS) inducing diabetic cardiomyopathy (DCM). ACE2 modulates cardioprotective activity not only by reducing deleterious Ang II signaling but also generating the protective peptide Ang-(1-7). Recently, several studies have reported that depletion of ACE2 worsens DCM, whereas ACE2 activation attenuates Ang II-induced cardiac dysfunction. In the present study, we aimed to evaluate the hypothesis that the enhancement of ACE2, using a US Food and Drug Administration (FDA)-approved ACE2 activator (diaminazene aceturate, DIZE), would have cardioprotective roles in a murine DCM. DIZE was administered intraperitoneally to male db/db mice (8 weeks old) for 8 weeks. Transthoracic echocardiography was used to assess cardiac mass and function in mice. Cardiac structure and fibrotic changes were examined using histology and immunohistochemistry. Gene and protein expression levels were examined using qRT-PCR and western blotting, respectively. Additionally, RNA sequencing was performed to investigate the underlying mechanisms of the effects of DIZE and identify novel potential therapeutic targets for DCM. DIZE prevented the diabetes mellitus-mediated structural and functional deterioration of mouse heart. Our findings suggest that the pharmacological activation of ACE2 could be a novel treatment strategy for DCM. We used the murine strain with db/db mice for assessing cardiac function in diabetic. db/db mice were separated with the vehilce group and the DIZE group which is administering DIZE.