Mdivi-1 attenuates oxidative stress and exerts vascular protection in ischemic/hypoxic injury by a mechanism independent of Drp1 GTPase activity

Hyperglycemia induces oxidative stress and plays a substantial role in the progression of vascular diseases. Here, we demonstrated the potentiality of peroxisome proliferator-activated receptor (PPAR)β/δ activation in attenuating high glucose-induced oxidative stress in endothelial cells and diabetic rats, pointing to the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2). HUVECs exposed to high glucose showed increased levels of reactive oxygen species (ROS) and upregulated NOX-2, NOX-4, Nrf2, and NQO-1 effects that were significantly reversed by the PPARβ/δ agonists GW0742 and L165041. Both PPARβ/δ agonists, in a concentration-dependent manner, induced transcriptional and protein upregulation of heme oxygenase-1 (HO-1) under low- and high-glucose conditions. All effects of PPARβ/δ agonists were reversed by either pharmacological inhibition or siRNA-based downregulation of PPARβ/δ. These in vitro findings were confirmed in diabetic rats treated with GW0742. In conclusion, PPARβ/δ activation confers vascular protection against hyperglycemia-induced oxidative stress by suppressing NOX-2 and NOX-4 expression plus a direct induction of HO-1; with the subsequent downregulation of the Nrf2 pathway. Thus, PPARβ/δ activation could be of interest to prevent the progression of diabetic vascular complications.

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Quercetin Improves Cardiomyocyte Vulnerability to Hypoxia by Regulating SIRT1/TMBIM6-Related Mitophagy and Endoplasmic Reticulum Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5529913 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Xing Chang ◽

Tian Zhang ◽

Qingyan Meng ◽

ShiyuanWang ◽

Peizheng Yan ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Endoplasmic Reticulum ◽

Cardiovascular Diseases ◽

Endoplasmic Reticulum Stress ◽

Oxygen Species ◽

Protective Effects ◽

Hypoxic Injury ◽

Human Cardiomyocytes ◽

Stress Damage

Cardiomyocyte apoptosis is an important pathological mechanism underlying cardiovascular diseases and is commonly caused by hypoxia. Moreover, hypoxic injury occurs not only in common cardiovascular diseases but also following various treatments of heart-related conditions. One of the major mechanisms underlying hypoxic injury is oxidative stress. Quercetin has been shown to exert antioxidant stress and vascular protective effects, making it a promising candidate for treating cardiovascular diseases. Therefore, we examined the protective effect of quercetin on human cardiomyocytes subjected to hypoxia-induced oxidative stress damage and its underlying mechanism. Human cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) in vitro with or without quercetin pretreatment; thereafter, flow cytometry, Cell Counting Kit-8 assay, laser scanning confocal microscopy, quantitative PCR, western blotting, and enzyme-linked immunosorbent assay were performed to analyze the effects of quercetin on cardiomyocytes. We found that H/R induced reactive oxygen species overproduction and endoplasmic reticulum stress, as well as inhibited the function of the mitochondria/endoplasmic reticulum and mitophagy, eventually leading to apoptosis and decreasing the viability of human cardiomyocytes. Quercetin pretreatment inhibited H/R-mediated overproduction of reactive oxygen species and damage caused by oxidative stress, increased mitophagy, regulated mRNA and protein expression of transmembrane BAX inhibitor-1 motif-containing 6 (TMBIM6), regulated endoplasmic reticulum stress, and improved the vulnerability of human cardiomyocytes to H/R. Furthermore, transfection with short interfering RNA against silent information regulator protein 1 (SIRT1) counteracted the protective effects of quercetin on cardiomyocytes. Thus, quercetin was predicted to regulate mitophagy and endoplasmic reticulum stress through SIRT1/TMBIM6 and inhibit H/R-induced oxidative stress damage. These findings may be useful for developing treatments for hypoxic injury-induced cardiovascular diseases and further highlight the potential of quercetin for regulating mitochondrial quality control and endoplasmic reticulum function.

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Dapagliflozin Restores Diabetes-Associated Decline in Vasculogenic Capacity of Endothelial Progenitor Cells via Activating AMPK-Mediated Inhibition of Inflammation and Oxidative Stress

10.21203/rs.3.rs-694662/v1 ◽

2021 ◽

Author(s):

Lifang Luo ◽

Bing Dong ◽

Jianning Zhang ◽

Yumin Qiu ◽

Xiaolin Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Vascular Complications ◽

Diabetic Patients ◽

Vascular Protection ◽

Endothelial Progenitor ◽

Ampk Signaling ◽

And Oxidative Stress

Abstract Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) provides added vascular protection beyond glucose lowering to patients with type 2 diabetes mellitus (T2DM). Endothelial progenitor cells (EPCs) are an important endogenous repair mechanism for diabetic vascular complications. Yet, whether SGLT2i protect vascular in diabetic patients by improving the function of EPCs remain to be elucidated. Methods: Sixty-three T2DM patients and 60 healthy participants were enrolled, and 15 of T2DM group taken dapagliflozin for 3 months. Retinal capillary density (RCD) and vasculogenic capacity of EPCs in vitro and in vivo were assessed among different groups. Genes related to inflammation/oxidative stress, and the AMPK signaling of EPCs in T2DM were determined before and after dapagliflozin treatment. Results: T2DM demonstrated a declined RCD and impaired vasculogenic capacity of EPCs. There is a linear correlation between RCD and the number of circulating EPCs. The expression of inflammation correlative genes was increased; however, anti-oxidative stress related genes expression was decreased in EPCs form T2DM, which were accompanied with reduced phosphorylation level of AMPK. Dapagliflozin treatment activated AMPK signaling, decreased the level of inflammation and oxidative stress, and rescued vasculogenic capacity of EPCs from T2DM. Furthermore, AMPK inhibitor pretreatment diminished the enhancement vasculogenic capacity of diabetic EPCs from dapagliflozin treatment.Conclusions: This study demonstrates for the first time that dapagliflozin restores vasculogenic capacity of EPCs via activating AMPK-mediated inhibition of inflammation and oxidative stress in T2DM.

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Does reversal of oxidative stress and inflammation provide vascular protection?

Cardiovascular Research ◽

10.1093/cvr/cvn354 ◽

2008 ◽

Vol 81 (4) ◽

pp. 649-659 ◽

Cited By ~ 56

Author(s):

K. K. Koh ◽

P. C. Oh ◽

M. J. Quon

Keyword(s):

Oxidative Stress ◽

Vascular Protection

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Involvement of bilitranslocase and beta-glucuronidase in the vascular protection by hydroxytyrosol and its glucuronide metabolites in oxidative stress conditions

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2018.02.121 ◽

2018 ◽

Vol 10 (2) ◽

pp. 231

Author(s):

J. Peyrol ◽

G. Meyer ◽

P. Obert ◽

O. Dangles ◽

L. Pechere ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Conditions ◽

Vascular Protection

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Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia

International Journal of Molecular Sciences ◽

10.3390/ijms21072504 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2504

Author(s):

Rahana Abd Rahman ◽

Padma Murthi ◽

Harmeet Singh ◽

Seshini Gurungsinghe ◽

Bryan Leaw ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Vascular Dysfunction ◽

Umbilical Vein ◽

In Vitro Study ◽

Activin A ◽

Hypoxic Injury ◽

Tnf Α ◽

Zona Occludens

In preeclampsia, widespread maternal endothelial dysfunction is often secondary to excessive generation of placental-derived anti-angiogenic factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), along with proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) and activin A, understanding of which offers potential opportunities for the development of novel therapies. The antimalarial hydroxychloroquine is an anti-inflammatory drug improving endothelial homeostasis in lupus. It has not been explored as to whether it can improve placental and endothelial function in preeclampsia. In this in vitro study, term placental explants were used to assess the effects of hydroxychloroquine on placental production of sFlt-1, sEng, TNF-α, activin A, and 8-isoprostane after exposure to hypoxic injury or oxidative stress. Similarly, human umbilical vein endothelial cells (HUVECs) were used to assess the effects of hydroxychloroquine on in vitro markers of endothelial dysfunction. Hydroxychloroquine had no effect on the release of sFlt-1, sEng, TNF-α, activin A, or 8-isoprostane from placental explants exposed to hypoxic injury or oxidative stress. However, hydroxychloroquine mitigated TNF-α-induced HUVEC production of 8-isoprostane and Nicotinanamide adenine dinucleotide phosphate (NADPH) oxidase expression. Hydroxychloroquine also mitigated TNF-α and preeclamptic serum-induced HUVEC monolayer permeability and rescued the loss of zona occludens protein zona occludens 1 (ZO-1). Although hydroxychloroquine had no apparent effects on trophoblast function, it may be a useful endothelial protectant in women presenting with preeclampsia.

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Effect of Systemic Triphenylphosphonium on Organ Function and Oxidative Stress

The American Surgeon ◽

10.1177/000313481808400119 ◽

2018 ◽

Vol 84 (1) ◽

pp. 36-42

Author(s):

Rebecca D. Powell ◽

Donna A. Goodenow ◽

A. Britton Christmas ◽

Iain H. Mckillop ◽

Susan L. Evans

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Antioxidant Activity ◽

Isolated Hepatocytes ◽

Male Rats ◽

Hypoxic Injury ◽

Endogenous Antioxidant ◽

Systemic Stress ◽

Species Production

Conditions of systemic stress can lead to increased reactive oxygen species production, mitochondrial dysfunction, systemic inflammation, and multiorgan dysfunction. Triphenylphosphonium (TPP1) is a lipophilic cation used to target therapeutics to mitochondria. We sought to determine the effects of TPP1 on mitochondrial integrity. Male rats were anesthetized and TPP1 (5 mg/kg) or vehicle (saline) was administered intravenously 30-minutes after anesthesia initiation and intraperitoneally (20 mg/kg) 60-minutes later. Rats were exsanguinated 2-hours postinjection. Cardiac, pulmonary, hepatic, splenic, and renal tissues were analyzed for inflammation, lipid peroxidation, endogenous antioxidant activity, cytokine expression, and mitochondrial function. In vitro modeling was performed using freshly isolated hepatocytes subjected to 8-hours hypoxia/30-minutes reoxygenation in the absence or presence of TPP1. TPP1 increased lipid peroxidation in the liver, lung, and kidney as well as antioxidant activity in the liver, kidney, and spleen. Conversely, antioxidant activity decreased in the lung with TPP1. In addition, TPP1 altered hepatic inflammatory mediators. In vitro, TPP1 attenuated oxygen consumption and, when combined with hypoxic injury, depolarized mitochondrial membranes in hepatocytes. TPP1 induces systemic responses associated with oxidative stress and worsening pathologies in animals. Caution should be exercised when employing TPP1 for therapeutics.

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