Intermittent High Glucose Implements Stress-Induced Senescence in Human Vascular Endothelial Cells: Role of Superoxide Production by NADPH Oxidase

Maeda, Morihiko; Hayashi, Toshio; Mizuno, Natsumi; Hattori, Yoshiyuki; Kuzuya, Masafumi

doi:10.1371/journal.pone.0123169

Cited by 91 publications

(77 citation statements)

References 36 publications

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“…Although the underlying cause of this link between T2D and monocyte ROS remains largely unknown, it has been proposed that factors from the circulating milieu are responsible for the induction of monocyte ROS in T2D (Jain et al , 2007; Huang et al , 2011; Lenin et al , 2012). A candidate is hyperglycemia, as many studies now demonstrate that high glucose causes increased expression of NADPH oxidase and subsequent ROS production in various cell types, including monocytes (Jain et al , 2007; Kuppan et al , 2010; Rodino-Janeiro et al , 2010; Huang et al , 2011; Maeda et al , 2015; Nagasu et al , 2016). However, other factors are likely involved.…”

Section: Discussionmentioning

confidence: 99%

Increased monocyte‐derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress

Restaino

Deo

Parrish

et al. 2017

Experimental Physiology

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Recent evidence suggests that exposure of human monocytes to glucolipotoxic media to mimic the composition of plasma of patients with type 2 diabetes (T2D) results in the induction of endoplasmic reticulum stress markers and formation of reactive oxygen species (ROS). The extent to which these findings translate to patients with T2D remains unclear. Thus, we first measured ROS (dihydroethidium fluorescence) in peripheral blood mononuclear cells (PBMCs) from whole blood of T2D patients (n=8) and compared to age matched healthy controls (n=8). T2D patients exhibited greater basal intracellular ROS (mean±SD, +3.4±1.4 fold; p<0.05) compared to controls. Next, increased ROS in PBMCs isolated from T2D patients was partially recapitulated in cultured human monocytes (THP-1 cells) exposed to plasma from T2D patients for 36 hours (+1.3±0.08 fold vs. plasma from controls; p<0.05). In addition, we found that increased ROS formation in THP-1 cells treated with T2D plasma was NADPH oxidase-derived and led to increased endothelial cell adhesion (+1.8±0.5 fold; p<0.05) and lipid uptake (+1.3±0.3 fold; p<0.05). Notably, we found that T2D plasma-induced monocyte ROS and downstream functional effects were abolished by treating cells with tauroursodeoxycholic acid, a chemical chaperone known to inhibit ER stress. Collectively, these data indicate that monocyte ROS production with T2D can be, in part, attributed to signals from the circulating environment. Furthermore, an interplay between ER stress and NADPH oxidase activity contributes to ROS production and may be a mechanism mediating endothelial cell adhesion and foam cell formation in T2D.

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Section: Discussionmentioning

confidence: 99%

Increased monocyte‐derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress

Restaino

Deo

Parrish

et al. 2017

Experimental Physiology

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“…According to previous studies, glucose fluctuations could induce more serious HUVEC dysfunction, which may be related to apoptosis (35,38,39) or senescence (28). But there is no research on the expression of autophagy, and the interval time of glucose fluctuations is always longer.…”

Section: Discussionmentioning

confidence: 99%

miR-1273g-3p participates in acute glucose fluctuation-induced autophagy, dysfunction, and proliferation attenuation in human umbilical vein endothelial cells

Guo

Sang

Yin

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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-Acute glucose fluctuations (AGF) often cause high mortality among critically ill patients, but the mechanisms induced by AGF are not clear. Recent studies suggest that endothelial dysfunction is a key factor that leads to high mortality among critically ill patients. Our goal is to evaluate the phenomenon and mechanisms of endothelial dysfunction induced by AGF. In this study, the functions of human umbilical vein endothelial cells (HUVECs) were compared after treatment with sustained high glucose (SHG), AGF in two groups (AGF1 fluctuations between 5 and 16 mM and AGF2 fluctuations between 5 and 25 mM), and normal glucose levels as a control group (CTR). The medium of the groups was changed every 4 h. The influence of AGF on wound healing was also tested on C57BL/6 mice. The results show that cell proliferation, angiogenesis, and migration functions were injured in the SHG and both AGF groups. AGF2 group shows the worse condition in vitro. In vivo, the wound healing was delayed after the AGF treatment. Furthermore, the markers of apoptosis and autophagy were analyzed. We observed that the autophagy changed in all treatment groups, but apoptosis showed no change. To get to know the mechanism of dysfunction and autophagy, we performed the microRNA chip assay and real-time PCR and found miR-1273g-3p remarkably changed in AGF2 group. After the mimic and inhibitor of miR-1273g-3p were transfected during the AGF2 treatment, we found that the dysfunction and autophagy were partially enhanced by miR-1273g-3p mimic and reversed by miR-1273g-3p inhibitor in AGF2 group. Thus, we conclude that AGF can induce more dysfunction and autophagy, and miR-1273g-3p is also an important factor that leads to the injury. glucose fluctuations; endothelial dysfunction; wound healing; autophagy; miR-1273g-3pINCREASING GLYCEMIC VARIABILITY can greatly increase the risk of mortality among critically ill patients. Several previous studies suggest that the variability in glucose levels over time is an important determinant of mortality among critically ill patients (21,22,58). Alternatively, recent evidence shows that glucose fluctuations may influence the development of diabetic complications(4, 47) and may produce more serious injury in organ functions than sustained high blood glucose. Krinsley and Preiser (20) reported that if a blood glucose range of 70 -140 mg/dl is maintained for Ͼ80% of the time, the chances of survival of nondiabetic critically ill adults will be greatly increased. Organ injury induced by glucose toxicity is commonly observed in both intensive care units and endocrine departments. The damage is also observed in in vitro cell culture and animal studies. Therefore, some authors have proposed that "glycemic variability" is a new therapeutic challenge in diabetes and the critical care setting (7).The mechanism of the production of glucose fluctuations is variable in several studies (35)(36)(37)(38)(39)57) in both preclinical and clinical research studies. However, this is not appropriate for the critically ill patient...

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“…In EC, GabaBet administration counteracted the oxidative stress induced by hGluc, by restoring the SOD activity and by negatively regulating p16 INK4A expression, a known marker of cellular senescence. 21 At the same time, GabaBet prevented the hGluc-induced downregulation of SIRT1, a member. of the sirtuin family with multiple roles in the modulation of the vascular function.…”

Section: Discussionmentioning

confidence: 97%

Gaba-betaine modulates SIRT1 and p16INK4A expression during high-glucose induced endothelial cell senescence

et al. 2017

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Gaba-betaine (γ-aminobutyric acid betaine, GabaBet), a betaine formed by trimethyllysine (TML), is a precursor of the L-carnitine biosynthesis. Betaine, quaternary ammonium compounds, are naturally occurring osmoprotectants or compatible solutes with a widespread distribution in plant and animal kingdoms. Among betaines, stachydrine (N,N-dimethyl-L-proline) (ProBet), abundant in citrus fruit juices, inhibits the deleterious effect of high-glucose (hGluc) on endothelial cells (EC). Hyperglycaemia induces endothelial dysfunction and vascular complications by promoting EC senescence, altering antioxidant enzyme involved in the system defence against reactive oxygen species (ROS), and limiting the cell proliferative potential. This study was designed to determine the possible effect of GabaBet against the hGluc-induced oxidative injury. Evaluation of cell viability revealed that GabaBet does not affect cell proliferation from 0.001 to 1mM up to 72 h. Of interest, co-treatment for 48 h with GabaBet (0.1 mM) and hGluc (30 mM) (GabaBet+hGluc) attenuated the EC growth arrest in the G0/G1 cell cycle phase. GabaBet counteracted the hGluc induced upregulation of p16 INK4A and the increased superoxide dismutase activity. Moreover, the downregulation of sirtuin 1 (SIRT1) expression, occurring under hGluc conditions, is significantly blocked by GabaBet. On the whole, results show that beneficial effects of GabaBet in the prevention of hGluc-induced endothelial senescence is paralleled by the modulation of SIRT1 and p16 INK4A expression levels.

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Intermittent High Glucose Implements Stress-Induced Senescence in Human Vascular Endothelial Cells: Role of Superoxide Production by NADPH Oxidase

Cited by 91 publications

References 36 publications

Increased monocyte‐derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress

Increased monocyte‐derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress

miR-1273g-3p participates in acute glucose fluctuation-induced autophagy, dysfunction, and proliferation attenuation in human umbilical vein endothelial cells

Gaba-betaine modulates SIRT1 and p16INK4A expression during high-glucose induced endothelial cell senescence

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