期刊
HYPERTENSION
卷 62, 期 4, 页码 746-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.113.01337
关键词
angiotensin-converting enzyme 2; diminazene; macrophages; myocardial infarction; stem cells
资金
- National Institutes of Health [HL056921, HL102033]
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. Diminazene aceturate (DIZE), a small molecule ACE2 activator, has been used to evaluate this hypothesis. DIZE (15 mg/kg per day, s.c.) was injected 2 days before MI surgery and continued throughout the study period. MI rats showed a 62% decrease in fractional shortening (%; control, 51.1 +/- 3.2; DIZE alone, 52.1 +/- 3.2; MI, 19.1 +/- 3.0), a 55% decrease in contractility (dP/dt(max) mm Hg/s; control, 9480 +/- 425.3; DIZE alone, 9585 +/- 597.4; MI, 4251 +/- 657.7), and a 27% increase in ventricular hypertrophy (mg/mm; control, 26.5 +/- 1.5; DIZE alone, 26.9 +/- 1.4; MI, 33.4 +/- 1.1). DIZE attenuated the MI-induced decrease in fractional shortening by 89%, improved dP/dt(max) by 92%, and reversed ventricular hypertrophy by 18%. MI also significantly increased ACE and angiotensin type 1 receptor levels but decreased ACE2 activity by 40% (control, 246.2 +/- 25.1; DIZE alone, 254.2 +/- 20.6; MI, 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. In addition, 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.
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