Diminazene Aceturate Enhances Angiotensin-Converting Enzyme 2 Activity and Attenuates Ischemia-Induced Cardiac Pathophysiology

Abstract

Angiotensin-converting enzyme 2 (ACE2) plays a critical role against myocardial infarction (MI). We hypothesized that activation of intrinsic ACE2 would be protective against ischemia-induced cardiac pathophysiology. Diminazine aceturate (DIZE), a small molecule ACE2 activator has been used to evaluate this hypothesis. DIZE (15 mg/kg/day, s.c.) was injected two days prior to MI surgery and continued throughout the study-period. MI rats showed a 62% decrease in fractional shortening (FS,%) [control (Con): 51.1 ± 3.2; DIZE alone (D) : 52.1 ± 3.2; MI (M): 19.1± 3.0], a 55% decrease in contractility (dP/dtmax mmHg/s) (Con: 9480 ± 425.3; D: 9585 ± 597.4; M: 4251 ± 657.7), and a 27% increase in ventricular hypertrophy [VH, mg/mm (Con: 26.5 ± 1.5; D: 26.9 ± 1.4; M: 33.4± 1.1)]. DIZE attenuated the MI-induced decrease in FS by 89%, improved dP/dtmax by 92%, and reversed VH by 18%. MI also significantly increased ACE and angiotensin type 1 receptor levels while decreased ACE2 activity by 40% (Con: 246.2 ± 25.1; D: 254.2 ± 20.6; M: 148.9 ± 29.2, RFU/min), which was reversed by DIZE treatment. Thus, DIZE treatment decreased the infarct area, attenuated LV remodeling post-MI and restored normal balance of the cardiac renin angiotensin system. Additionally, DIZE treatment increased circulating endothelial progenitor cells, increased engraftment of cardiac progenitor cells and decreased inflammatory cells in peri-infarct cardiac regions. All of the beneficial effects associated with DIZE treatment were abolished by C-16, an ACE2 inhibitor. Collectively, DIZE and DIZE-like small molecules may represent promising new therapeutic agents for MI.

Angiotensin-Converting Enzyme 2 (ACE2) Activator Diminazene Aceturate Ameliorates Endotoxin-Induced Uveitis in Mice

“…Our study provides the first experimental evidence that DIZE can activate ACE2 and such activation plays an anti-inflammatory role in ocular inflammation model. Moreover, previous studies have demonstrated that DIZE activates ACE2 and the beneficial effects by DIZE are abolished by ACE2/Ang-(1-7)/Mas antagonists, 26,28,45 suggesting that these beneficial effects are mediated by activating the ACE2/Ang-(1-7)/Mas axis. In fact the antiinflammatory effects of DIZE in most recent studies 43,46 may also involve the ACE2/Ang-(1-7)/Mas axis, since Ang IImediated signaling is known to activate MAPK and the NF-jB signaling pathway.…”

Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

“…Recently, ACE2 priming by the pharmacological activator, xanthenone (XNT), has been shown to protect the function of endothelial progenitor cells in hypertension and diabetes (5,11,18,23). In the present study, we have used a newly discovered ACE2 activator, DIZE (20,40,46), and shown that it enhances ACE2 activity in vitro. Chronic DIZE treatment elevated the activity of local vascular ACE2, subsequently increased the production of Ang (1-7), and augmented both EDRs in conduit aortas and FMD in resistance arteries from db/db mice.…”

Peptidases and the Renin-Angiotensin System: The Alternative Angiotensin-(1-7) Cascade

“…Chronic treatment with DIZE ameliorated the extent of pulmonary hypertensin and fibrosis, renal tissue injury, and myocardial infarction consistent with enhanced levels of Ang-(1-7) and a reduction in Ang II [84,[87][88][89][90]. Interestingly, DIZE treatment was also associated with increased mRNA levels of ACE2 suggesting that DIZE may exhibit actions apart from the direct activation of the peptidase [87,91]. However, it should be noted that the effects of DIZE on ACE2 activity or expression have not been confirmed by others.…”

“…In regard to the benefits of an activated ACE2 pathway, several compounds have been identified that may act as allosteric activators of ACE2 including xanthenone (XNT) and diminazene aceturate (DIZE) to promote a higher ratio of Ang-(1-7) to Ang II [86]. Chronic treatment with DIZE ameliorated the extent of pulmonary hypertensin and fibrosis, renal tissue injury, and myocardial infarction consistent with enhanced levels of Ang-(1-7) and a reduction in Ang II [84,[87][88][89][90]. Interestingly, DIZE treatment was also associated with increased mRNA levels of ACE2 suggesting that DIZE may exhibit actions apart from the direct activation of the peptidase [87,91].…”