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Effects of Trimetazidine on PDCD4/NF-κB/TNF-α Pathway in Coronary Microembolization
Qiang Su1,2, Lang Li1, Jinmin Zhao3,2
1Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Background/Aims:
The local inflammatory response caused by coronary microembolization (CME) is the primary cause of progressive cardiac dysfunction. The PDCD4/NF-κB/TNF-α signaling pathway plays a significant role in CME-induced myocardial Inflammation. Trimetazidine (TMZ) reduces myocardial injury, caused by percutaneous coronary intervention, through relieving the CME-induced myocardial systolic dysfunction. Therefore, the present study investigated the role of TMZ pre-treatment in the protection of myocardium after CME and PDCD4/NF-κB/TNF-α in mini pigs.
Methods:
20 Bama mini pigs were randomized into sham operation (sham), microembolization (CME), TMZ, and siRNA-PDCD4 groups (n = 5). The CME model was established by injecting polyethylene microspheres via microcatheter into the left anterior descending coronary artery. The TMZ group was injected 2.5 mg/kg drug via ear vein 30 min before CME; whereas, the siRNA-PDCD4 group was transfected with PDCD4 siRNA at the left anterior descending coronary artery via microcatheter 72h before CME. Cardiac function indexes were measured using cardiac echocardiography. The mRNA expression of PDCD4 and TNF-α in the myocardium was detected by quantitative fluorescence PCR, and the protein expression of PDCD4, NF-κB (p65), and TNF-α by Western blot.
Results:
Echocardiographic parameters showed lower cardiac function and higher serum cTnI level in the CME group than sham, which was manifested as reduced left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS), cardiac output (CO), and increased left ventricular diastolic diameter (LVEDd). Compared to the CME group, the CME-induced cardiac function injury was reduced, and the serum cTnI level was decreased in the TMZ and siRNA-PDCD4 groups. The expressions of PDCD4, NF-κB (p65), and TNF-α were significantly increased in the CME than the sham groups (P < 0.05), and significantly decreased in the TMZ and siRNA-PDCD4 groups than the CME group (P < 0.05).
Conclusion:
TMZ pretreatment effectively reduced the myocardial damage caused by CME via inhibiting the PDCD4/NF-κB/ TNF-α pathway in cardiomyocytes.
Insights
Trimetazidine (TMZ) pre-treatment protects the heart from microembolization injury by inhibiting the PDCD4/NF-κB/TNF-α pathway. This study in mini pigs demonstrates TMZ
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Coronary microembolization (CME) causes local inflammation, leading to progressive cardiac dysfunction.
- The PDCD4/NF-κB/TNF-α signaling pathway is implicated in CME-induced myocardial inflammation.
- Trimetazidine (TMZ) is known to reduce myocardial injury from percutaneous coronary intervention by alleviating CME-induced systolic dysfunction.
Purpose of the Study:
- To investigate the protective effects of TMZ pre-treatment on myocardium following CME.
- To elucidate the role of the PDCD4/NF-κB/TNF-α pathway in TMZ's cardioprotective mechanism against CME in mini pigs.
Main Methods:
- A coronary microembolization (CME) model was established in 20 Bama mini pigs, randomized into sham, CME, TMZ, and siRNA-PDCD4 groups.
- Cardiac function was assessed using echocardiography, and myocardial expression of PDCD4, NF-κB (p65), and TNF-α was analyzed via quantitative PCR and Western blot.
- TMZ was administered intravenously 30 minutes before CME, while PDCD4 siRNA was delivered via microcatheter 72 hours prior to CME.
Main Results:
- CME significantly impaired cardiac function (reduced LVEF, FS, CO; increased LVEDd) and elevated serum cTnI levels compared to sham.
- TMZ and siRNA-PDCD4 treatments attenuated CME-induced cardiac dysfunction and reduced serum cTnI levels.
- Expressions of PDCD4, NF-κB (p65), and TNF-α were significantly upregulated in the CME group and downregulated in the TMZ and siRNA-PDCD4 groups.
Conclusions:
- TMZ pre-treatment effectively mitigates myocardial damage induced by CME.
- The cardioprotective effect of TMZ is mediated through the inhibition of the PDCD4/NF-κB/TNF-α pathway in cardiomyocytes.
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