Oscillating glucose and constant high glucose induce endoglin expression in endothelial cells: the role of oxidative stress

Sala, Lucia La; Pujadas, Gemma; Nigris, Valeria De; Canivell, Sílvia; Novials, Anna; Genovese, Stefano; Ceriello, Antonio

doi:10.1007/s00592-014-0670-3

Cited by 42 publications

(31 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glucose‐induced oxidative damage is a well‐established phenomenon in the initiation and progression of chronic diabetic complications (Chen et al, ; Feng et al, ; Mortuza et al, ). The findings on oxidative damage from our study are in keeping with previous demonstrations by others and us (Chen et al, ; La Sala et al, ). The novel aspects of this study are the demonstration of mitochondrial SIRTs and their regulation by specific miRs in mediating such effects.…”

Section: Discussionsupporting

confidence: 94%

“…As mitochondrial oxidative stress is a key initiating event in glucose‐induced cellular damage, we used 8‐OHdG as a marker of oxidative DNA damage. We and others have used this sensitive and specific approach previously (Farhangkhoee et al, ; La Sala et al, ). Indeed, glucose caused oxidative DNA damage, as evidenced by increased nuclear staining.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Glucose‐induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs

et al. 2020

View full text Add to dashboard Cite

Diabetic complications cause significant morbidity and mortality. Dysfunction of vascular endothelial cells (ECs), caused by oxidative stress, is a main mechanism of cellular damage. Oxidative stress accelerates EC senescence and DNA damage. In this study, we examined the role of mitochondrial sirtuins (SIRTs) in glucose‐induced oxidative stress, EC senescence, and their regulation by miRNAs. Human retinal microvascular endothelial cells (HRECs) were exposed to 5 mmol/L (normoglycemia; NG) or 25 mmol/L glucose (hyperglycemia; HG) with or without transfection of miRNA antagomirs (miRNA‐1, miRNA‐19b, and miRNA‐320; specific SIRT‐targeting miRNAs). Expressions of SIRT3, 4 and 5 and their targeting miRNAs were examined using qRT‐PCR and ELISAs were used to study SIRT proteins. Cellular senescence was investigated using senescence‐associated β‐gal stain; while, oxidative stress and mitochondrial alterations were examined using 8‐OHdG staining and cytochrome B expressions, respectively. A streptozotocin‐induced diabetic mouse model was also used and animal retinas and hearts were collected at 2 months of diabetes. In HRECs, HG downregulated the mRNAs of SIRTs, while SIRT‐targeting miRNAs were upregulated. ELISA analyses confirmed such downregulation of SIRTs at the protein level. HG additionally caused early senescence, endothelial‐to‐mesenchymal transition and oxidative DNA damage in ECs. These changes were prevented by the transfection of specific miRNA antagomirs and by resveratrol. Retinal and cardiac tissues from diabetic mice also showed similar reductions of mitochondrial SIRTs. Collectively, these findings demonstrate a novel mechanism in which mitochondrial SIRTs regulate glucose‐induced cellular aging through oxidative stress and how these SIRTs are regulated by specific miRNAs. Identifying such mechanisms may lead to the discovery of novel treatments for diabetic complications.

show abstract

Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Glucose‐induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Moreover, one-year visit-to-visit glucose variability predicted development of end stage renal disease in T2DM patients [ 34 ] and was independently associated with the presence of cardiovascular autonomic neuropathy in patients with inadequately controlled T2DM [ 35 ]. In our previous study we found that in oscillating and high glucose, total endoglin, its soluble form (sENG), KLF-6 and HIF-1 α were significantly increased [ 36 ], and glucose variability reduction via continuous subcutaneous insulin infusion in T1DM increases circulating EPCs levels, suggesting a novel mechanism of vascular damage by oscillating glucose [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Oscillating glucose induces microRNA-185 and impairs an efficient antioxidant response in human endothelial cells

Sala

Cattaneo

Nigris

et al. 2016

Cardiovasc Diabetol

Self Cite

View full text Add to dashboard Cite

BackgroundIntracellular antioxidant response to high glucose is mediated by Cu/Mn-superoxide dismutases (SOD-1/SOD-2), catalase (CAT) and glutathione peroxidases (GPx), particularly glutathione peroxidase-1 (GPx-1). Although oscillating glucose can induce a more deleterious effect than high glucose on endothelial cells, the mechanism by which oscillating glucose exerts its dangerous effects is incompletely understood; however, the involvement of oxidative damage has been generally accepted. In this study we sought to determine whether oscillating glucose differentially modulates antioxidant response, and to elucidate the potential regulatory mechanisms exerted by the microRNA-185 (miR-185).MethodsHuman endothelial cells were exposed for 1 week to constant and oscillating high glucose. SOD-1, SOD-2, CAT and GPx-1, as well as two markers of oxidative stress [8-hydroxy-2′-deoxyguanosine (8-OHdG) and the phosphorylated form of H2AX (γ-H2AX)] were measured at the end of the experiment. Intracellular miR-185 was measured and loss-of function assays were performed in HUVEC. Bioinformatic tool was used to predict the link between miR-185 on 3′UTR of GPx-1 gene. Luciferase assay was performed to confirm the binding on HUVEC.ResultsAfter exposure to constant high glucose SOD-1 and GPx-1 increased, while in oscillating glucose SOD-1 increased and GPx-1 did not. SOD-2 and CAT remained unchanged under both conditions. A critical involvement of oscillating glucose-induced miR-185 in the dysregulation of endogenous GPx-1 was found. Computational analyses predict GPx-1 as miR-185′s target. HUVEC cultures were used to confirm glucose’s causal role on the expression of miR-185, its target mRNA and protein and finally the activation of antioxidant response. In vitro luciferase assays confirmed computational predictions targeting of miR-185 on 3′-UTR of GPx-1 mRNA. Knockdown of miR-185, using anti-miR-185 inhibitor, was accompanied by a significant upregulation of GPx-1 in oscillating glucose. 8-OHdG and γ-H2AX increased more in oscillating glucose than in constant high glucose.ConclusionsGlucose oscillations may exert more deleterious effects on the endothelium than high glucose, likely due to an impaired response of GPx-1, coupled by the upregulation of miR-185.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0390-9) contains supplementary material, which is available to authorized users.

show abstract

“…Hypoxia and oxidative stress are considered triggers of S-endoglin release, which, in turn, inhibits the anti-atherogenic effects induced by TGF-β (32,33). Although a more recent study has demonstrated that increased S-endoglin level per se is not capable of inducing ED in an animal model, the authors indicated that their finding does not rule out the possibility that S-endoglin might contribute to alteration of endothelial function in the presence of other risk factors related to CVDs (34).…”

Section: Discussionmentioning

confidence: 99%

Soluble Endoglin Level Increase Occurs Prior to Development of Subclinical Structural Vascular Alterations in Diabetic Adolescents

Emeksiz

Bıdecı²,

Damar³

et al. 2016

Jcrpe

View full text Add to dashboard Cite

Objective:Soluble endoglin (S-endoglin) has been implicated as a potential marker of endothelial dysfunction (ED) and was reported to be elevated in diabetic adults, correlating with the severity of diabetic vasculopathy. However, circulating S-endoglin and its association with other markers of ED have not been formerly analyzed in the first decade of diabetes onset in adolescents with type 1 diabetes mellitus (T1DM).Methods:Fifty-eight adolescents with moderately/poorly controlled T1DM were included in this study and twenty-nine healthy adolescents served as controls. The diabetic group was divided into two groups based on the presence of microalbuminuria, as the microalbuminuria group (n=15) and the normoalbuminuria group (n=43). Functional vascular alterations were evaluated by measuring serum S-endoglin and plasma nitric oxide (NO) concentrations, the flow-mediated dilatation (FMD) of the brachial artery. Carotid intima media thickness (CIMT) was measured for evaluation of structural vascular alterations.Results:The S-endoglin and NO levels of both microalbuminuria and normoalbuminuria groups were higher than those of the control group (for S-endoglin, p=0.047 and p<0.001; for NO, p=0.004 and p=0.006, respectively). The FMD percent was lower in the microalbuminuria group compared to the normoalbuminuria and control groups (p=0.036 and p=0.020, respectively). There were negative correlations between S-endoglin concentration and FMD percent (r=-0.213, p=0.051) and between serum S-endoglin concentration and albumin excretion rate (r=-0.361, p=0.005). No significant differences were found in CIMT among any of the groups (p=0.443).Conclusion:In adolescents with T1DM, S-endoglin concentrations might increase in parallel to the deterioration in endothelial function before subclinical structural vascular alterations become evident.

show abstract

Oscillating glucose and constant high glucose induce endoglin expression in endothelial cells: the role of oxidative stress

Abstract: Together, these findings provide novel clue about endoglin in the regulation of high glucose-mediated vascular damage in HUVECs and the role of oxidative stress in this regulation.

Cited by 42 publications

References 41 publications

Glucose‐induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs

Glucose‐induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs

Oscillating glucose induces microRNA-185 and impairs an efficient antioxidant response in human endothelial cells

Soluble Endoglin Level Increase Occurs Prior to Development of Subclinical Structural Vascular Alterations in Diabetic Adolescents

Contact Info

Product

Resources

About