Trimetazidine Protects Against Atherosclerosis by Changing Energy Charge and Oxidative Stress

Zheng, Shuzhan; Du, Yanfei; Peng, Qing; Fan, Xiaoxuan; Li, Jiafu; Chen, Mao

doi:10.12659/msm.911317

Cited by 16 publications

(20 citation statements)

References 45 publications

(48 reference statements)

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“…Notably, TMZ reduces the levels of markers of oxidative stress and increases SOD activity in human aortic smooth muscle cells (152) and decreases MDA levels in blood sample from young and aged rats (151). In this regard, one mechanism by which TMZ may modulate the redox balance is the inhibition of the b-oxidation (45), thus favoring glucose metabolism and reducing ROS production.…”

Section: Fig 5 Exercise Modu-mentioning

confidence: 99%

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

Penna

Ballarò

Costelli

2020

Antioxidants & Redox Signaling

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Significance: The management of cancer patients is frequently complicated by the occurrence of a complex syndrome known as cachexia. It is mainly characterized by muscle wasting, a condition that associates with enhanced protein breakdown and with negative energy balance. While the mechanisms underlying cachexia have been only partially elucidated, understanding the pathogenesis of muscle wasting in cancer hosts is mandatory to design new targeted therapeutic strategies. Indeed, most of cancer patients will experience cachexia during the course of their disease, and about 25% of cancer-related deaths are due to this syndrome, rather than to the tumor itself. Recent Advances: Compelling evidence suggests that an altered redox homeostasis likely contributes to cancerinduced muscle protein depletion, directly or indirectly activating the intracellular degradative pathways. In addition, oxidative stress impinges on both mitochondrial number and function; the other way round, altered mitochondria lead to enhanced redox imbalance, creating a vicious loop that eventually results in negative energy metabolism. Critical Issues: The present review focuses on the possibility that pharmacological and nonpharmacological strategies able to restore a physiologic redox balance could be useful components of treatment schedules aimed at counteracting cancer-induced muscle wasting. Future Directions: Exercise and the use of exercise mimetic drugs represent the most promising approaches capable of reinforcing the muscle antioxidant defenses of cancer patients. The results from ongoing and new clinical trials are needed to validate the preclinical studies and provide effective therapies for cancer cachexia.

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Section: Fig 5 Exercise Modu-mentioning

confidence: 99%

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

Penna

Ballarò

Costelli

2020

Antioxidants & Redox Signaling

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“…TMZ is reported to exert its protective effects through various mechanisms. It prevents diabetic cardiomyopathy by inhibiting NOX2/TrPC3-induced oxidative stress [ 37 ], and protects against atherosclerosis by reducing reactive oxygen species production and regulating smooth muscle proliferation [ 38 ]. In addition, TMZ has also been implicated in the regulation of mitochondrial metabolism, mitochondrial biosynthesis, and mitochondrial fission/fusion [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Trimetazidine enhances myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice through directly activating Akt and promoting the binding of HSF1 to VEGF-A promoter

et al. 2022

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Latest clinical research shows that trimetazidine therapy during the perioperative period relieves endothelial dysfunction in patients with unstable angina induced by percutaneous coronary intervention. In this study we investigated the effects of TMZ on myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery. TAC mice were administered trimetazidine (2.8 mg/100 µL, i.g.) for 28 consecutive days. We showed that trimetazidine administration significantly increased blood vessel density in the left ventricular myocardium and abrogated cardiac dysfunction in TAC mice. Co-administration of a specific HSF1 inhibitor KRIBB11 (1.25 mg/100 µL, i.h.) abrogated the angiogenesis-promoting effects of trimetazidine in TAC mice. Using luciferase reporter and electrophoretic mobility shift assays we demonstrated that the transcription factor HSF1 bound to the promoter region of VEGF-A, and the transcriptional activity of HSF1 was enhanced upon trimetazidine treatment. In molecular docking analysis we found that trimetazidine directly bound to Akt via a hydrogen bond with Asp292 and a pi–pi bond with Trp80. In norepinephrine-treated HUVECs, we showed that trimetazidine significantly increased the phosphorylation of Akt and the synergistic nuclear translocation of Akt and HSF1, as well as the binding of Akt and HSF1 in the nucleus. These results suggest that trimetazidine enhances myocardial angiogenesis through a direct interaction with Akt and promotion of nuclear translocation of HSF1, and that trimetazidine may be used for the treatment of myocardial angiogenic disorders in hypertensive patients.

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“…Salicylate has been shown to bind the same sites as A-769662 to improve lipid homeostasis in isolated cells and animal models via activation of AMPK [ 19 , 20 ]. As there is abundant evidence of the role of the drug candidates selected, these were summarised, tabulated, and referenced for ease ( Supplemental Table S1 [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]).…”

Section: Discussionmentioning

confidence: 99%

Inducing Energetic Switching Using Klotho Improves Vascular Smooth Muscle Cell Phenotype

Docherty

Strembitska

Baker

et al. 2021

IJMS

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The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke. Comparing wild-type VSMCs from an ApoE model of atherosclerosis with a flox’d Pink1 knockout of inducible mitochondrial dysfunction we show WT Pink1 is essential for normal cell viability, while Klotho mediates energetic switching which may preserve cell survival. Methods: Wild-type ApoE VSMCs were screened to identify potential drug candidates that could improve longevity without inducing cytotoxicity. The central regulator of cell metabolism AMP Kinase was used as a readout of energy homeostasis. Functional energetic switching between oxidative and glycolytic metabolism was assessed using XF24 technology. Live cell imaging was then used as a functional readout for the WT drug response, compared with Pink1 (phosphatase-and-tensin-homolog (PTEN)-induced kinase-1) knockout cells. Results: Candidate drugs were assessed to induce pACC, pAMPK, and pLKB1 before selecting Klotho for its improved ability to perform energetic switching. Klotho mediated an inverse dose-dependent effect and was able to switch between oxidative and glycolytic metabolism. Klotho mediated improved glycolytic energetics in wild-type cells which were not present in Pink1 knockout cells that model mitochondrial dysfunction. Klotho improved WT cell survival and migration, increasing proliferation and decreasing necrosis independent of effects on apoptosis. Conclusions: Klotho plays an important role in VSMC energetics which requires Pink1 to mediate energetic switching between oxidative and glycolytic metabolism. Klotho improved VSMC phenotype and, if targeted to the plaque early in the disease, could be a useful strategy to delay the effects of plaque ageing and improve VSMC survival.

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Trimetazidine Protects Against Atherosclerosis by Changing Energy Charge and Oxidative Stress

Cited by 16 publications

References 45 publications

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

Trimetazidine enhances myocardial angiogenesis in pressure overload-induced cardiac hypertrophy mice through directly activating Akt and promoting the binding of HSF1 to VEGF-A promoter

Inducing Energetic Switching Using Klotho Improves Vascular Smooth Muscle Cell Phenotype

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