GW24-e2319 CB2 receptor agonist AM1241 promoted the Infarcted murine heart repair by activating endogenuous cardiac stem/progenitor cells

Objectives The aim of this study was to investigate the ability of CB2 agonist AM1241 to promote murine infarcted myocardium repair by activating resident endogenous cardiac stem/progenitor cells (CSC/CPCs) and possible mechanisms. Methods Acute myocardial infarction (AMI) was induced in mice by ligation of left descending artery. Mice were randomised into following groups with n = 10 each: (1) Sham group, (2) MI group, (3) MI + AM1241 group, (4) MI + AM1241 + AM630 (CB2 receptor antagonist). Then, AM1241(10mg/kg) was intraperitoneal injected into mice for seven consecutive days. Three days post-operation, cardiomyocyte survival and apoptosis was determined by Ki67 and TUNEL staining respectively. The levels of LDH, TNF-α and IL-6 were examined with ELISA assay. The express-ion of CSC/CPCs markers c-kit and Runx1 in infarction border zones (IBZs) of myocardium were evaluated with immohistopathology 7 days later. The mice cardiac function evaluation was performed by echocardiography 3, 7, 14 and 28 days postoperation respectively. Myocardium fibrosis was detected with Masson’s trichrome stain 4 weeks later. The expression of ERK, Keap-1, Nrf2 and heme oxygenase (HO-1) and superoxide dismutase (Cu/Zn-SOD) were performed by Western blot analysis. Results In contrast to sham group, AM1241 could significantly increase c-kit and Runx1 positive CSC/CPCs number [Runx 1 positive cells: (3.32 + 0.25)% vs. (1.14 + 0.13)%, p < 0.01], improve cardiomyocytes survival [Ki67 positive cells: (35.32 + 2.03)% vs. (8.94 + 0.79)%, p < 0.01) and inhibit them apoptosis (p < 0.05), and decrease serum levels of LDH as well as the concertration of TNF-α and IL-6 in injury myocardium (p < 0.05). Meanwhile, AM1241 could ameliorate left venricular ejection fraction (LVEF) and fractional shortening (FS) 14 and 28 days post-operation (p < 0.05), and reduce fibrosis (p < 0.01). Moreover, AM1241 treatment also markedly increased p-ERK, HO-1 and Cu/Zn-SOD expression, promoted Nrf-2 nuclear transocation, but decreased Keap-1 expression (p < 0.05). However, AM630 abolished these beneficial roles of AM1241. In contrast to sham group, AM1241 could significantly increase c-kit and Runx1 positive CSC/CPCs number [Runx 1 positive cells: (3.32 + 0.25)% vs. (1.14 + 0.13)%, p < 0.01], improve cardiomyocytes survival [Ki67 positive cells: (35.32 + 2.03)% vs. (8.94 + 0.79)%, p < 0.01) and inhibit them apoptosis (p < 0.05), and decrease serum levels of LDH as well as the concertration of TNF-α and IL-6 in injury myocardium (p < 0.05). Meanwhile, AM1241 could ameliorate left venricular ejection fraction (LVEF) and fractional shortening (FS) 14 and 28 days post-operation (p < 0.05), and reduce fibrosis (p < 0.01). Moreover, AM1241 treatment also markedly increased p-ERK, HO-1 and Cu/Zn-SOD expression, promoted Nrf-2 nuclear transocation, but decreased Keap-1 expression (p < 0.05). However, AM630 abolished these beneficial roles of AM1241. Conclusions AM1241 could better adverse oxidative stress and inflammation milieu after AMI, benefit CSC/CPCs activation, induce myocardial regeneration, and improve cardiac function, which might be associated with ERK/Nrf 2/ARE signaling pathway activation.