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GW24-e2319 CB2 receptor agonist AM1241 promoted the Infarcted murine heart repair by activating endogenuous cardiac stem/progenitor cells
  1. Wang Yabin,
  2. Dongjuan Wang,
  3. Wenxing Hu,
  4. Jiangwei Chen,
  5. Feng Cao
  1. Department of Cardiology, Xijing Hospital, Fourth Millitary Medical University, Xi’an, Shaan Xi, China

Abstract

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.

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