Angiotensin-converting enzyme 2 ameliorates diabetic cardiomyopathy by reducing reactive oxidative stress

Abstract

Diabetic cardiomyopathy (DCM) is a phenomenon characterized by a deterioration in cardiac function and structure, independent of vascular complications. Among many possible causes, the renin-angiotensinaldosterone system and angiotensin II have been proposed as major drivers of DCM development. Angiotensin-converting enzyme2(ACE2) is the main key for reducing angiotensin Ⅱ(AngⅡ) in the reninangiotensin-aldosterone system(RAAS) including diabetic cardiomyopathy(DCM). ACE2 modulates cardioprotective activity not only by reducing deleterious AngⅡ but also by generating the protective peptide Ang-1-7. Recently, several studies have reported that depletion of ACE2 worsens DCM, whereas ACE2 activation attenuates AngⅡ 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. Male db/db mice aged 8 weeks received DIZE intraperitoneally for 8 weeks. Mice were examined using transthoracic echocardiography to determine their heart mass and function. Histology and immunohistochemistry were used to analyze the structure of the heart and fibrotic alterations. Western blotting and qRT-PCR were used to analyze the levels of gene and protein expression. Furthermore, we tried to find the new ACE2 agonists based on the screening, which was a phenylalanine assay and flow cytometry. During the screening, the No. 49 chemical was identified as novel ACE2 agonists for further investigation. For conclusion, DIZE prevented the morphological and functional decline of the mouse heart caused by diabetes mellitus. Our results indicate that ACE2 might be a novel treatment strategy for DCM.