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. 2015 Apr 1;8(4):3735-41.
eCollection 2015.

Trimetazidine protects against hypoxia-reperfusion-induced cardiomyocyte apoptosis by increasing microRNA-21 expression

Qiong Yang  1 , Kan Yang  1 , An-Ying Li  1
Affiliations

Trimetazidine protects against hypoxia-reperfusion-induced cardiomyocyte apoptosis by increasing microRNA-21 expression

Qiong Yang et al. Int J Clin Exp Pathol. .

Abstract

Myocardial tissue injury caused by ischemia and hypoxia is a major cause of fatal diseases, including coronary atherosclerosis resulting from myocardial infarction and stroke. Trimetazidine (TMZ), as an anti-ischemic and antioxidant agent, has been demonstrated to preventing ischemia/reperfusion-induced cardiomyocyte apoptosis. However, the anti-apoptosis mechanism of TMZ has not been fully elucidated. The present study demonstrated that miR-21 involved trimetazidine-induced anti-apoptosis during H/R injury in H9C2 cell. In this study, TMZ increased miR-21 expression which further upregulated the Akt signaling activity via suppressing the expression of phosphatase and tensin homolog (PTEN) in H/R H9C2 cell. The increased activity of Akt signaling decreased the ratio of Bax/Bcl-2 and the expression of caspase-3 and inhibited H/R induced apoptosis. In conclusion, this study revealed the mechanism that TMZ up-regulated miR-21 expression, then miR-21 targeted PTEN increasing the PI3K pathway and finally the activation of this pathway counteracted the apoptotic effect of hypoxia/reperfusion.

Keywords: H/R injury; PTEN/Akt pathway; Trimetazidine; miR-21.

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Figures

Figure 1
Figure 1
miR-21 regulated PTEN and p-AKT expression. miR-21 mimics or inhibitor was transfected into the H9C2 cells, respectively. NC means negative control group. Protein expression of PTEN (A) and p-AKT (B) were examined by western blot analysis, respectively (aP<0.05 vs. NC group).
Figure 2
Figure 2
Role of TMZ in H/R-treated H9C2 cells. The H9C2 cells were randomly assigned into three groups: Sham group, in which the cells were treated with 0μM TMZ for 48 h and then cultured under normal oxygenation conditions (5% CO2, and 95% air); H/R group, in which cells were treated with 0 μM TMZ for 48 h and then cultured under H/R conditions; and H/R+TMZ group, in which cells were treated with 10 μM TMZ for 48 h and then subjected to H/R treatment. (A) qRT-PCR assay determined the relative expression of miR-21. Protein expression of PTEN (B) and p-AKT (C) were examined by western blot analysis, respectively (aP<0.01 and bP<0.05 vs. sham group, cP<0.05 vs. H/R group).
Figure 3
Figure 3
miR-21 involved the regulation of TMZ on PTEN and p-AKT expression in HR-treated H9C2 cells. The H9C2 cells were assigned into four groups: sham group, in which the cell were treated with 0 μM TMZ for 48 h and then cultured under normal oxygenation conditions (5% CO2, and 95% air); H/R group, in which cells were treated with 0 μM TMZ for 48 h and then cultured under H/R conditions; and H/R+TMZ group, in which cells were treated with 10 μM TMZ for 48 h and then subjected to H/R treatment; H/R+TMZ+ inhibitors group, in which cells were transfected with 50 nM miR-21 inhibitors, next, treated with 10 μM TMZ for 48 h and finally subjected to H/R treatment. Protein expression of PTEN (A) and p-AKT (B) were examined by western blot analysis, respectively. aP<0.01 vs. sham group, bP<0.01 and cP<0.05 vs. H/R group, dP<0.01 vs. H/R+TMZ+NC group.
Figure 4
Figure 4
siPTEN and IGF-1 affected the expression of PTEN and p-AKT. Ser group, cells were treated with 50 nM scramble control siPTEN for 18 h. siPTEN group, cells were treated with siPTEN. IGF-1 group, cells were treated with IGF-1. Protein expression of PTEN (A) and p-AKT (B) were examined by western blot analysis, respectively. aP<0.01 vs. control group, bP<0.01 vs. Ser group.
Figure 5
Figure 5
TMZ, miR-21, PTEN and p-AKT involved the regulation of H/R-induced apoptosis in H9C2 cells. H/R, cells were treated with H/R. TMZ, cells were treated with 10 μM TMZ for 48 h. NC, cells were treated with 0 μM TMZ. miR-21 inhibitor, cells were transfected with 50 nM miR-21 inhibitor. Ser, cells were treated with 50 nM scramble control siPTEN for 18 h. siPTEN, cells were treated with 50 nM siPTEN for 18 h. IGF-1, cells were treated with 10 nM for 12 h. A and B. caspase-3, Bax and Bcl-2 expression were examined by western blot analysis, respectively. (aP<0.01 vs. sham group, bP<0.01 and cP<0.05 vs. H/R group, dP<0.01 and eP<0.05 vs. H/R+TMZ group, cP<0.05 vs. H/R+TMZ+miR-21 inhibitor group).
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