Trimetazidine mitigates high glucose-induced retinal endothelial dysfunction by inhibiting PI3K/Akt/mTOR pathway-mediated autophagy

Yang, Qingsong; Li, Sizhen; Zhou, Zhenyu; Yang, Xiaodong; Liu, Yating; Hao, Kuanxiao; Fu, Min

doi:10.1080/21655979.2022.2048993

Cited by 15 publications

(8 citation statements)

References 41 publications

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“…Some studies have found that high glucose promotes endothelial proliferation, invasion and angiogenesis (Li et al, 2016;Fang and Chang, 2021;Wang et al, 2022;Yang et al, 2022). Our investigation focussed on HRMECs cultured under high glucose conditions for over 60 days, while most previous studies exposed cells for a maximum of 2 weeks.…”

Section: Discussionmentioning

confidence: 99%

Long term high glucose exposure induces premature senescence in retinal endothelial cells

et al. 2022

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Purpose: Features of cellular senescence have been described in diabetic retinal vasculature. The aim of this study was to investigate how the high glucose microenvironment impacts on the senescence program of retinal endothelial cells.Methods: Human retinal microvascular endothelial cells were cultured under control and high glucose conditions of 5 mM and 25 mM D-glucose, respectively. Isomeric l-glucose was used as the osmotic control. Cells were counted using CASY technology until they reached their Hayflick limit. Senescence-associated β-Galactosidase was used to identify senescent cells. Endothelial cell functionality was evaluated by the clonogenic, 3D tube formation, and barrier formation assays. Cell metabolism was characterized using the Seahorse Bioanalyzer. Gene expression analysis was performed by bulk RNA sequencing. Retinal tissues from db/db and db/+ mice were evaluated for the presence of senescent cells. Publicly available scRNA-sequencing data for retinas from Akimba and control mice was used for gene set enrichment analysis.Results: Long term exposure to 25 mM D-Glucose accelerated the establishment of cellular senescence in human retinal endothelial cells when compared to 5 mM D-glucose and osmotic controls. This was shown from 4 weeks, by a significant slower growth, higher percentages of cells positive for senescence-associated β-galactosidase, an increase in cell size, and lower expression of pRb and HMGB2. These senescence features were associated with decreased clonogenic capacity, diminished tubulogenicity, and impaired barrier function. Long term high glucose-cultured cells exhibited diminished glycolysis, with lower protein expression of GLUT1, GLUT3, and PFKFB3. Transcriptomic analysis, after 4 weeks of culture, identified downregulation of ALDOC, PFKL, and TPI1, in cells cultured with 25 mM D-glucose when compared to controls. The retina from db/db mice showed a significant increase in acellular capillaries associated with a significant decrease in vascular density in the intermediate and deep retinal plexuses, when compared to db/+ mice. Senescent endothelial cells within the db/db retinal vasculature were identified by senescence-associated β-galactosidase staining. Analysis of single cell transcriptomics data for the Akimba mouse retina highlighted an enrichment of senescence and senescence-associated secretory phenotype gene signatures when compared to control mice.Conclusion: A diabetic-like microenvironment of 25 mM D-glucose was sufficient to accelerate the establishment of cellular senescence in human retinal microvascular endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Long term high glucose exposure induces premature senescence in retinal endothelial cells

et al. 2022

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“…Autophagy also dually moderates apoptosis and angiogenesis [ 24 , 25 ]. In one viewpoint, autophagy maintains cell survivability through blocking the Akt signaling pathway [ 72 , 73 ]. Contradictorily, another view argued that autophagy was reserved by activating the Akt signaling pathway [ 28 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin Activates Autophagy to Regulate Apoptosis and Angiogenesis of Periodontal Ligament Stem Cells via the Akt/ERK1/2/BAD Signaling Pathway under Inflammatory Microenvironment

Huang

Lei

et al. 2022

Stem Cells International

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Background. Angiogenic tissue engineering is a vital problem waiting to be settled for periodontal regeneration. Erythropoietin, a multieffect cytokine, has been reported as a protective factor for cell fate. According to our previous study, erythropoietin has a significantly angiogenic effect on periodontal ligament stem cells. To further explore its potential effects and mechanism, we studied biological behaviors of periodontal ligament stem cells under inflammatory microenvironment induced by different concentrations (0, 10, 20, 50, and 100 ng/mL) of tumor necrosis factor-α (TNF-α) and examined how different concentrations (0, 5, 10, 20, and 50 IU/mL) of erythropoietin changed biological behaviors of periodontal ligament stem cells. Materials and Methods. Cell Counting Kit-8 was used for cell proliferation assay. Annexin V-PI-FITC was used for cell apoptosis through flow cytometry. Matrigel plug was adopted to measure the angiogenic capacity in vitro. RNA sequencing was used to detect the downstream signaling pathway. Quantitative real-time polymerase chain reaction was conducted to examine mRNA expression level. Western blot and immunofluorescence were applied to testify the protein expression level. Results. Periodontal ligament stem cells upregulated apoptosis and suppressed autophagy and angiogenesis under inflammatory microenvironment. Erythropoietin could activate autophagy to rescue apoptosis and angiogenesis levels of periodontal ligament stem cells through the Akt/Erk1/2/BAD signaling pathway under inflammatory microenvironment. Conclusions. Erythropoietin could protect periodontal ligament stem cells from inflammatory microenvironment, which provided a novel theory for periodontal regeneration.

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“…Consequently, trimetazidine facilitates endothelial cell proliferation as part of the neovascularization process, ultimately improving endothelial function. However, in hyperglycemic conditions, the drug alleviates angiogenesis in retinal endothelial cells, as evidenced by reduced cell migration and invasion, decreased tube formation, and VEGF expression [ 79 ]. In diabetic retinopathy, characterized by an abnormal increase in angiogenesis, trimetazidine reverses these detrimental effects [ 79 ].…”

Section: Effects Of Trimetazidine On Endothelial Cell and Vascular Sm...mentioning

confidence: 99%

“…However, in hyperglycemic conditions, the drug alleviates angiogenesis in retinal endothelial cells, as evidenced by reduced cell migration and invasion, decreased tube formation, and VEGF expression [ 79 ]. In diabetic retinopathy, characterized by an abnormal increase in angiogenesis, trimetazidine reverses these detrimental effects [ 79 ]. The findings of these studies suggest that trimetazidine modulates pathological angiogenesis.…”

Section: Effects Of Trimetazidine On Endothelial Cell and Vascular Sm...mentioning

confidence: 99%

“…Evidence suggests that inhibition of HSF1 abolishes the beneficial effects of trimetazidine in endothelial cells [ 78 ]. In diabetic retinopathy, trimetazidine modulates angiogenesis by activating the PI3K/Akt/mTOR signaling pathway [ 79 ]. This, in turn, suppresses autophagy—a cellular process responsible for breaking down and recycling damaged or unnecessary components within cells, thereby maintaining cellular health and adapting to stress [ 72 ].…”

Section: Effects Of Trimetazidine On Endothelial Cell and Vascular Sm...mentioning

confidence: 99%

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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 mitigates high glucose-induced retinal endothelial dysfunction by inhibiting PI3K/Akt/mTOR pathway-mediated autophagy

Cited by 15 publications

References 41 publications

Long term high glucose exposure induces premature senescence in retinal endothelial cells

Long term high glucose exposure induces premature senescence in retinal endothelial cells

Erythropoietin Activates Autophagy to Regulate Apoptosis and Angiogenesis of Periodontal Ligament Stem Cells via the Akt/ERK1/2/BAD Signaling Pathway under Inflammatory Microenvironment

Role of Trimetazidine in Ameliorating Endothelial Dysfunction: A Review

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