title: 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. 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/dtmax 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/dtmax 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.
authors: Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610. mraizada@ufl.edu.
authors: Yanfei
authors: Y
authors: Qi
authors: Juan
authors: J
authors: Zhang
authors: Colleen T
authors: CT
authors: Cole-Jeffrey
authors: Vinayak
authors: V
authors: Shenoy
authors: Andrew
authors: A
authors: Espejo
authors: Mina
authors: M
authors: Hanna
authors: Chunjuan
authors: C
authors: Song
authors: Carl J
authors: CJ
authors: Pepine
authors: Michael J
authors: MJ
authors: Katovich
authors: Mohan K
authors: MK
authors: Raizada
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004133:Diminazene / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D009203:Myocardial Infarction / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects
chemical_list: D044140:Receptor, Angiotensin, Type 1; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C003915:diminazene aceturate; D004133:Diminazene
keywords: angiotensin-converting enzyme 2; diminazene; macrophages; myocardial infarction; stem cells
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