Effects of Trimetazidine on PDCD4/NF-κB/TNF-α Pathway in Coronary Microembolization

Abstract

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.

Modulating the metabolism by trimetazidine enhances myoblast differentiation and promotes myogenesis in cachectic tumor-bearing c26 mice

“…Additionally, a deeper analysis of the effects of TMZ during C2C12 differentition shows that the transcript levels of factors involved in myotube hypotrophy, namely atrogin-1/MAFbx and myostatin, decrease in TMZ-treated C2C12 myoblasts cultured in DM for 24h, to progressively return to control levels at 48h and 72h (Figure 4E ), while MuRF-1 mRNA levels are not affected by TMZ in the same conditions (Figure 4E ). We speculate that, since TMZ inhibits NF-kB [ 53 , 54 ] which is related to Atrogin expression, this might cause a reduction of Atrogin [ 55 ]. However, this point needs to be elucidated by additional studies.…”

Trimetazidine in Heart Failure

“…Trimetazidine has anti-inflammatory effects and has been shown to significantly decrease the levels of serum inflammatory markers (IL-1 β, IL-6, and TNF-α) (Zhou et al, 2012). In the model of coronary artery microembolism in Guangzhou Bama miniature pigs, inflammatory markers, such as PDCD4, NF-kB, and TNF-α, were shown to increase by 4-8 fold (Su et al, 2017) and were shown to decrease by about 40% following treatment with trimetazidine. Trimetazidine combined with coenzyme Q10 is effective against viral myocarditis (Shao et al, 2016) and alleviates septic myocardial damage induced by endotoxin by activating sirt1 (Chen et al, 2016) and promoting the migration of central granulocytes (Chen et al, 2018).…”

Down-Regulation of PDCD4 Promotes Proliferation, Angiogenesis and Tumorigenesis in Glioma Cells

“…Previous studies showed that the expression of PDCD4 suppresses NF-kB transcriptional activation by inhibiting localization of p65 (Hwang et al, 2014;Su et al, 2017). To confirm whether the over-expression of PDCD4 reduces the nuclear translocation of the NF-κB subunit, we fractionated the cell lysates over-expressing PDCD4 into nuclear and cytoplasmic fractions, and then tested the subcellular localization of NF-κB subunits, viz.…”