Background: ACE2 [vasoprotective axis of the renin angiotensin system (RAS)], plays a protective role in cardiovascular diseases. In addition, the number and function of EPCs is impaired in heart failure. These observations led us to hypothesize that DIZE would protect against myocardial infarction (MI) and improve EPC function.
Methods: DIZE treatment (15 mg/kg/day, s.c.) was initiated in 8-week-old SD rats two days prior to MI surgery and continued throughout the study-period. Cardiac function was measured four weeks post-MI. The number of circulating rat EPCs (CD4-/CD5-/CD8-/CD90+) was quantified via flow cytometry. EPCs were isolated from spleen mononuclear cells and function was assessed by ability to migrate towards SDF-1.
Results: MI rats showed a 58% decrease in fractional shortening (FS,%) [control (C): 54.6 ± 3.0; DIZE alone (D) : 52.5± 4.8; MI: 22.5± 3.7], a 50% decrease in contractility (dP/dtmax mmHg/s) (C: 9480 ± 425.3; D: 9585 ± 597.4; MI: 4716 ± 724.9), and a 27% increase in ventricular hypertrophy (VH, mg/mm) (C: 26.5 ± 1.5; D: 26.9 ± 1.4; MI: 33.4± 1.1). This was associated with 40% decrease in cardiac ACE2 activity (C: 246.2 ± 25.1; D: 254.2 ± 20.6; MI: 148.9 ± 29.2, RFU/min). There was a 23% decrease in the number of circulating EPCs (C: 4.3 ± 0.1%; D: 4.2 ± 0.2%; MI: 3.3 ± 0.1%) and 12% decrease in their migratory ability (MI: 20.0%). DIZE resulted in a 2.5 fold increase in ACE2 activity in MI heart, attenuated the MI-induced decrease in FS by 49%, improved dP/dtmax by 49%, and reversed VH by 21%. In addition, DIZE increased the number of EPCs by 21% and improved their migratory ability by 9% in the MI rats. Furthermore, immunostaining for Islet-1, a marker for cardiac progenitor cells (CPCs) demonstrated that DIZE increased CPC number and decreased infiltration of macrophages in the peri-infarct area of the ischemic heart. All these beneficial effects were abolished by C-16, an ACE2 inhibitor.
Conclusions: Collectively, our observations demonstrate that activation of endogenous ACE2 improves cardiac function and attenuates LV remodeling post-MI, increases EPC number and function, increases engraftment of CPCs and decreases inflammatory cells in peri-infarct cardiac regions. Thus, DIZE may represent a promising therapeutic strategy for treating MI.