Regulatory effects of trimetazidine in cardiac ischemia/reperfusion injury

Farzaei, Mohammad Hosein; Ramezani-Aliakbari, Fatemeh; Ramezani-Aliakbari, Maryam; Zarei, Mohammad; Komaki‬, Alireza; Shahidi, Siamak; Sarihi, Abdolrahman; Salehi, Iraj

doi:10.1007/s00210-023-02469-7

Cited by 7 publications

(4 citation statements)

References 170 publications

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“…We rst assessed the cardioprotective effects of TMZ. Similar to previous studies [55], in vitro TMZ pretreatment enhanced cell viability and reduced LDH release and oxidative stress in H9C2 cells with A/R injury. In vivo, TMZ partially restored the reduction in LVEF, LVFS, and ESV and reduced the myocardial injury marker enzymes, myocardial ber morphology, and infarct area after I/R in rats.…”

Section: Discussionsupporting

confidence: 88%

Trimetazidine Attenuates Ischemia/Reperfusion-Induced Myocardial Ferroptosis by Modulating the Sirt3/Nrf2-GSH System and Reducing Mitochondrial Oxidative Stress

Tan,

Yin,

Chen

et al. 2023

Preprint

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Background and Purpose： Ferroptosis is a newly defined mode of cellular demise. Increasing investigatieon supports the hypothesis that ferroptosis is a crucial factor in the complex mechanisms of myocardial ischemia-reperfusion(I/R) injury. Hence, the pursuit of ferroptosis as a therapeutic approach has promise in the management of myocardial damage. Although evidence suggests that trimetazidine (TMZ) is potentially efficacious against myocardial injury, the exact mechanism of this efficacy is yet to be fully elucidated. The objective of this work is to determine whether TMZ can act as a ferroptosis resistor and affect I/R-mediated myocardial injury. Methods： We constructed in vitro and in vivo models of I/R using H9C2 cardiomyocytes, primary cardiomyocytes, and SD rats. The optimal concentration of TMZ was determined by CCK8 and LDH experiments. Ferroptosis was confirmed by detecting the levels of GSH, lipid peroxidation ,and Fe2+, and the morphological alterations of mitochondria under transmission electron microscopy. Western blotting, RT-qPCR, and immunofluorescence staining were performed to detect the expression of iron death-related markers, including GPX4, SLC7A11, ACSL4, TFRC, and FTH. The Sirt3/Nrf2 pathway, which is associated with ferroptosis, was detected by Western blotting. We investigated the effects of Sirt3 molecules on TMZ-mediated inhibition of ferroptosis and cardioprotection by interfering with Sirt3 expression or activity using si-Sirt3 or 3-TYP (inhibitor of Sirt3 activity). Results: I/R mediated the onset of myocardial ferroptosis in vitro and in vivo, as reflected by excessive iron aggregation, GSH depletion, and the increase in lipid peroxidation. TMZ largely reversed this alteration and attenuated myocardium injury. Mechanistically, TMZ upregulated the expression of Sirt3. The use of si-Sirt3 and 3-TYP partly mitigated the inhibitory effect of TMZ on I/R-mediated ferroptosis and upregulated the expression of Nrf2 and its downstream target, GPX4-SLC7A11. Conclusions: TMZ attenuates I/R-mediated ferroptosis by activating the Sirt3-Nrf2/GPX4/SLC7A11 signaling pathway.

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Section: Discussionsupporting

confidence: 88%

Trimetazidine Attenuates Ischemia/Reperfusion-Induced Myocardial Ferroptosis by Modulating the Sirt3/Nrf2-GSH System and Reducing Mitochondrial Oxidative Stress

Tan,

Yin,

Chen

et al. 2023

Preprint

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“…Trimetazidine has been shown to suppress inflammatory events in various animal models of atherosclerosis and diabetes ( Table 6 ) [ 10 , 11 , 12 ]. Its anti-inflammatory effects have been reported in many studies, including muscle atrophy and mercury-induced nephrotoxicity models [ 65 , 66 , 69 ] It is believed the drug exerts its anti-inflammatory effect via inhibition of the NOD-like receptor family pyrin domain containing 3/gasdermin D (NLRP3/GSDMD) pathway, AMP-activated protein kinase (AMPK), and galectin-3 [ 66 , 69 , 70 ].…”

Section: Effects Of Trimetazidine On Oxidative Stress and Inflammationmentioning

confidence: 99%

Role of Trimetazidine in Ameliorating Endothelial Dysfunction: A Review

Kamisah,

Che Hassan

2024

Pharmaceuticals

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Endothelial dysfunction is a hallmark of cardiovascular diseases, contributing to impaired vasodilation, altered hemodynamics, and atherosclerosis progression. Trimetazidine, traditionally used for angina pectoris, exhibits diverse therapeutic effects on endothelial dysfunction. This review aims to elucidate the mechanisms underlying trimetazidine’s actions and its potential as a therapeutic agent for endothelial dysfunction and associated cardiovascular disorders. Trimetazidine enhances vasodilation and hemodynamic function by modulating endothelial nitric oxide synthase activity, nitric oxide production, and endothelin-1. It also ameliorates metabolic parameters, including reducing blood glucose, mitigating oxidative stress, and dampening inflammation. Additionally, trimetazidine exerts antiatherosclerotic effects by inhibiting plaque formation and promoting its stability. Moreover, it regulates apoptosis and angiogenesis, fostering endothelial cell survival and neovascularization. Understanding trimetazidine’s multifaceted mechanisms underscores its potential as a therapeutic agent for endothelial dysfunction and associated cardiovascular disorders, warranting further investigation for clinical translation.

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“…Trimetazidine (TMZ) alleviates MI/R injury by regulating autophagy through the AKT/mTOR and AMPK/mTOR pathways in MI/R H9c2 cells and SD rats. An in vitro study also demonstrated that TMZ administration mitigated oxidative stress and increased antioxidant enzymes by enhancing the CSE/H 2 S pathway activity before H/R in H9c2 cells [ 157 ]. The beneficial effects of Hongjingtian injection (HJT) in treating MI/R are partially due to improved mitochondrial function and regulated autophagy, which inhibit cell apoptosis through the AMPK/mTOR pathway.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

“…TMZ alleviates MI/R injury by regulating autophagy. At the cellular level, TMZ exerts anti-ischemic effects on the heart by shifting the cardiac substrate preference from fatty acid oxidation to glucose [ 157 ]. Metformin had the dual effects of promoting both cytoplasmic AMPKα1- and nuclear AMPKα2-related signaling to improve autophagic flux and restore cardiac function in MI/R mice [ 181 ].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Crosstalk among Reactive Oxygen Species, Autophagy and Metabolism in Myocardial Ischemia and Reperfusion Stages

Peng,

Tao,

Liu

et al. 2023

Aging and disease

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Myocardial ischemia is the most common cardiovascular disease. Reperfusion, an important myocardial ischemia tool, causes unexpected and irreversible damage to cardiomyocytes, resulting in myocardial ischemia/reperfusion (MI/R) injury. Upon stress, especially oxidative stress induced by reactive oxygen species (ROS), autophagy, which degrades the intracellular energy storage to produce metabolites that are recycled into metabolic pathways to buffer metabolic stress, is initiated during myocardial ischemia and MI/R injury. Excellent cardioprotective effects of autophagy regulators against MI and MI/R have been reported. Reversing disordered cardiac metabolism induced by ROS also exhibits cardioprotective action in patients with myocardial ischemia. Herein, we review current knowledge on the crosstalk between ROS, cardiac autophagy, and metabolism in myocardial ischemia and MI/R. Finally, we discuss the possible regulators of autophagy and metabolism that can be exploited to harness the therapeutic potential of cardiac metabolism and autophagy in the diagnosis and treatment of myocardial ischemia and MI/R.

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Regulatory effects of trimetazidine in cardiac ischemia/reperfusion injury

Cited by 7 publications

References 170 publications

Trimetazidine Attenuates Ischemia/Reperfusion-Induced Myocardial Ferroptosis by Modulating the Sirt3/Nrf2-GSH System and Reducing Mitochondrial Oxidative Stress

Trimetazidine Attenuates Ischemia/Reperfusion-Induced Myocardial Ferroptosis by Modulating the Sirt3/Nrf2-GSH System and Reducing Mitochondrial Oxidative Stress

Role of Trimetazidine in Ameliorating Endothelial Dysfunction: A Review

Crosstalk among Reactive Oxygen Species, Autophagy and Metabolism in Myocardial Ischemia and Reperfusion Stages

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