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. 2016 Nov;14(5):4216-4222.
doi: 10.3892/mmr.2016.5773. Epub 2016 Sep 26.

Trimetazidine protects against cardiac ischemia/reperfusion injury via effects on cardiac miRNA‑21 expression, Akt and the Bcl‑2/Bax pathway

Ning Ma  1 , Jingyun Bai  2 , Weihua Zhang  1 , Hong Luo  1 , Xin Zhang  1 , Donghai Liu  1 , Chenhui Qiao  1
Affiliations

Trimetazidine protects against cardiac ischemia/reperfusion injury via effects on cardiac miRNA‑21 expression, Akt and the Bcl‑2/Bax pathway

Ning Ma et al. Mol Med Rep. 2016 Nov.

Abstract

Trimetazidine is a piperazine-derived metabolic agent, which exerts cell protective effects and has been reported to be efficient in the treatment of chronic stable angina pectoris. In addition, it has been shown to exert protection against acute myocardial infarction. The present study aimed to investigate whether trimetazidine protects against cardiac ischemia/reperfusion (I/R) injury, and to determine whether its curative effects are associated with microRNA (miRNA)‑21 expression, Akt, and the B‑cell lymphoma 2 (Bcl‑2)/Bcl‑2‑associated X protein (Bax) pathway. Cardiac I/R injury was induced by ligating the left anterior descending coronary artery in adult rats. Subsequently, cardiac function was evaluated, and the expression levels of miRNA‑21, Bcl‑2, Bax and phosphorylated‑Akt were detected using quantitative polymerase chain reaction and western blotting. The results indicated that trimetazidine was able to significantly protect cardiac function and reduce infarct size in rats following cardiac I/R injury. Furthermore, trimetazidine significantly promoted miRNA‑21 expression and phosphorylated‑Akt protein expression, and reduced the Bcl‑2/Bax ratio in rats following cardiac I/R injury. Knockdown of miRNA‑21 using anti‑miR‑21 plasmids was able to reverse the protective effects of trimetazidine against cardiac I/R injury. These results indicated that miRNA‑21 serves a protective role in cardiac I/R injury via Akt and the Bcl‑2/Bax pathway. In addition, trimetazidine exerts protective effects against cardiac I/R injury through cardiac miRNA‑21 expression, Akt, and the Bcl‑2/Bax pathway. Therefore, the present study provided evidence regarding the protective effects of miRNA‑21 on cardiac I/R injury following treatment with trimetazidine in vivo.

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Figures

Figure 1.
Figure 1.
Chemical structure of trimetazidine.
Figure 2.
Figure 2.
Trimetazidine protects cardiac function. Trimetazidine exerts protective effects against (A) CK and (B) LDH activities in rats following cardiac I/R injury. ##P<0.05 vs. control group; **P<0.05 vs. I/R group. Con, control group; C-TMZ, control-trimetazidine group; I/R, cardiac ischemia/reperfusion injury model group; TMZ, trimetazidine (30 mg/kg) treatment group; CK, casein kinase; LDH, lactate dehydrogenase.
Figure 3.
Figure 3.
Trimetazidine reduces infarct size. ##P<0.05 vs. control group; **P<0.05 vs. I/R group. Con, control group; C-TMZ, control-trimetazidine group; I/R, cardiac ischemia/reperfusion injury model group; TMZ, trimetazidine (30 mg/kg) treatment group.
Figure 4.
Figure 4.
Trimetazidine activates miRNA-21 expression. ##P<0.05 vs. control group; **P<0.05 vs. I/R group. Con, control group; C-TMZ, control-trimetazidine group; I/R, cardiac ischemia/reperfusion injury model group; TMZ, trimetazidine (30 mg/kg) treatment group; miRNA/miR-21, microRNA-21. .
Figure 5.
Figure 5.
Trimetazidine activates Akt protein expression. P-Akt protein expression was detected in rats following cardiac I/R injury (A) using western blotting, and (B) the results were statistically analyzed. ##P<0.05 vs. control group; **P<0.05 vs. I/R group. Con, control group; C-TMZ, control-trimetazidine group; I/R, cardiac ischemia/reperfusion injury model group; TMZ, trimetazidine (30 mg/kg) treatment group; p-, phosphorylated.
Figure 6.
Figure 6.
Trimetazidine suppresses Bcl-2/Bax protein expression. (A and B) Bcl-2 and (C and D) Bax protein expression levels were detected following cardiac I/R injury using (A and C) western blotting, and (B and D) the results were statistically analyzed. ##P<0.05 vs. control group; **P<0.05 vs. I/R group. Con, control group; C-TMZ, control-trimetazidine group; I/R, cardiac ischemia/reperfusion injury model group; TMZ, trimetazidine (30 mg/kg) treatment group; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein.
Figure 7.
Figure 7.
Knockdown of cardiac miRNA-21 expression affects the protective effect of trimetazidine. Knockdown of cardiac miRNA-21 expression affects (A) miRNA-21 expression, and the protective effects of trimetazidine against (B) CK and (C) LDH activities in anoxia-induced H9c2 cells. ##P<0.05 vs. control group; **P<0.05 vs. TMZ group. Control, miR-NC-transfected group; TMZ, trimetazidine treatment group; anti-miRNA-21, anti-miRNA-21-transfected group; CK, casein kinase; LDH, lactate dehydrogenase; miRNA/miR-21, microRNA-21.
Figure 8.
Figure 8.
Knockdown of cardiac miR-21 expression affects p-Akt protein expression. (A) P-Akt protein expression was detected following miRNA-21 knockdown in anoxia-induced H9c2 cells using western blotting, and (B) the results were statistically analyzed. ##P<0.05 vs. control group; **P<0.05 vs. TMZ group. Control, miR-NC-transfected group; TMZ, trimetazidine treatment group; anti-miRNA-21, anti-miRNA-21-transfected group; miRNA-21, microRNA-21; p-, phosphorylated.
Figure 9.
Figure 9.
Knockdown of cardiac miRNA-21 expression affects on Bcl-2/Bax protein expression. (A and B) Bcl-2 and (C and D) Bax protein expression levels were detected following miRNA-21 knockdown in anoxia-induced H9c2 cells (A and C) using western blotting, and (B and D) the results were statistically analyzed. ##P<0.05 vs. control group; **P<0.05 vs. TMZ group. Control, miR-NC-transfected group; TMZ, trimetazidine treatment group; anti-miRNA-21, anti-miRNA-21-transfected group; miRNA-21, microRNA-21; Bcl-2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein.
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