Biphasic response of endothelial progenitor cell proliferation induced by high glucose and its relationship with reactive oxygen species

Zhang, Wei; Wang, Xinhong; Chen, SF; Zhang, Guoping; Lü, Nonghua; Hu, Renming; Jin, Hongyue

doi:10.1677/joe-08-0036

Cited by 12 publications

(12 citation statements)

References 18 publications

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“…25) Inhibition of oxidative stress has reversed diabetic EPC dysfunction, suggesting that increased ROS plays key roles in diabetic vascular impairment. 5,25,26) The increased level of ROS in EPCs was also detected under HG condition, 27) and here we further demonstrated the enhanced mitochondrial ROS and disruption of mitochondrial membrane potential in HG-exposed EPCs, suggesting its role in HG-induced autophagy in EPCs. Mitochondrial ROS generation and subsequent mitochondrial oxidative damage may modulate mitophagy, a form of micro-autophagy, potentially contributing to autophagic cell death.…”

Section: Discussionsupporting

confidence: 78%

High Glucose Condition Induces Autophagy in Endothelial Progenitor Cells Contributing to Angiogenic Impairment

Kim

Shin

Akram

et al. 2014

Biological & Pharmaceutical Bulletin

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Key words endothelial progenitor cell; high glucose; autophagy; oxidative stress; diabetes; mitochondria In patients with diabetes mellitus, cardiovascular dysfunction is one of the major complications, accounting for upto 80% of deaths. 1) Not only for the mortality, it is also a main cause for the disability in diabetes, where impaired peripheral circulation results in delayed wound healing and lower limb amputation. 2) Nevertheless, the complete mechanisms of the vascular pathogenesis in diabetic condition remain to be established.The role of endothelial progenitor cells (EPCs) in the vascularization has been identified, 3) suggesting that impaired EPC function may contribute to vascular complications under disease states. Of note, clinical observations demonstrated that the number of circulating EPCs is decreased, and their functions are impaired in diabetes. 4,5) In vivo diabetic animal studies revealed that EPC functions of mobilization, differentiation and tube formation are disrupted, 5,6) implying that EPC dysfunction could be critical for defective diabetic angiogenesis. Although several studies have given explanations including increased oxidative stress and impaired nitric oxide signaling, 7) the mechanisms underlying diabetic EPC dysfunction are still largely unknown.Autophagy, a homeostatic process that involves in organelle recycling and protein degradation, is essential for normal cellular physiology. It is upregulated in response to extra-or intra-cellular signals such as starvation and endoplasmic reticulum (ER) stress, to preserve the balance between biosynthesis and turnover. 8) The importance of autophagy has been highlighted based on the observation that defective autophagy plays a significant role in human pathologies. 9) Nevertheless, autophagy plays a double-sided role in pathological states, and excessive autophagy is linked to cellular dysfunction, preceding cell death. 9) Detrimental intracellular changes such as impaired mitochondrial function, oxidative stress, and accumulation of protein aggregates can result in autophagic cell damage. 9,10) Interestingly, impaired function of vascular cells can also be mediated by autophagy. Autophagy in endothelial cells was induced by methylglyoxal, a metabolite specific to diabetes. 11) Despite the important role of EPCs in angiogenesis and vascular regeneration, studies regarding the autophagic regulation in EPCs are very limited. Wang et al. recently observed that hypoxia induced autophagy in EPCs,12) suggesting the role of autophagy in survival of the transplanted EPCs. To our best knowledge, the autophagic alteration in EPCs under pathological conditions has not been investigated.Here, we demonstrated that pathological stress of high glucose (HG) condition increased the autophagic marker in bonemarrow derived EPCs (BM-EPCs), which is correlated to the functional impairment. Mitochondrial damage and generation of oxidative stress were increased in HG-exposed EPCs. With this study, we believe that an important evidence for the role of autopha...

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Section: Discussionsupporting

confidence: 78%

High Glucose Condition Induces Autophagy in Endothelial Progenitor Cells Contributing to Angiogenic Impairment

Kim

Shin

Akram

et al. 2014

Biological & Pharmaceutical Bulletin

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“…It has been known that low baseline levels of ROS produced in response to tissue ischemia serve as intracellular signaling molecules to prevent tissue injury and promote angiogenesis [24,25], but excess amounts of ROS impair EPC function and induce vascular injury [26]. Previous studies also showed that HG and AGEs induced ROS production and overexpressed oxidant stress in EPCs and other cell types [12,13,14,27,28]. Inflammatory markers such as TNF-α and CRP also caused vascular dysfunction [29] and the reduction and dysfunction of EPCs [30,31,32], and HG and AGEs induced IL-6 and TNF-α expression [33,34].…”

Section: Discussionmentioning

confidence: 99%

“…This study aimed to investigate how HG and AGEs regulate the expression of miR-126. Previous studies have shown that HG and AGEs adversely affect EPC function, which may be related to reactive oxygen species (ROS) [12,13,14], so we also aimed to investigate whether miR-126 mediates the effects of HG and AGEs on EPCs in relation to ROS as well as inflammatory markers. The findings will help the understanding of the mechanism of EPC dysfunction and vascular disease in DM.…”

Section: Introductionmentioning

confidence: 99%

Hyperglycemia and Advanced Glycation End Products Regulate miR-126 Expression in Endothelial Progenitor Cells

Zhou²,

Pei³

et al. 2016

J Vasc Res

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Background/Aims: Dysfunction of endothelial progenitor cell (EPCs) contributes to diabetic vascular disease. We reported that downregulated miR-126 in diabetic patients causes EPC dysfunction. The study was designed to investigate how high glucose (HG) and advanced glycation end products (AGEs) regulate miR-126 expression and whether miR-126 mediates the effects of HG and AGEs on EPCs. Methods: We first tested the effects of glucose (5.5-50 mM) and AGEs at 50-200 mg/l on EPC proliferation and selected HG at 50 mM and AGEs at 50 mg/l for further experiments. EPCs were stimulated with HG and AGEs, and miR-126 expression was measured by real-time PCR. Reactive oxygen species (ROS) were measured by immunofluorescence microscopy and flow cytometry. IL-6 and TNF-α levels in EPC supernatants were determined by ELISA. The effects of miR-126 on ROS and inflammatory markers under stimulation of HG and AGEs were also assessed. Finally, the effects of inhibitors of PI3K and Akt on AGE-mediated miR-126 expression were examined. Results: HG and AGEs increased IL-6, TNF-α and ROS and decreased miR-126 expression in EPCs. miR-126 negatively regulated IL-6, TNF-α and ROS. miR-126 overexpression reduced and miR-126 inhibition further increased the inflammatory markers and ROS induced by HG and AGEs. Inhibitors of PI3K and Akt further decreased miR-126 expression in the presence of AGEs. Conclusions: In conclusion, hyperglycemia and AGEs decrease miR-126 expression in EPCs. Recovering miR-126 expression may protect EPCs against dysfunction induced by HG and AGEs.

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“…On the other hand, ROS generated in response to hyperglycemia (Zhang et al, 2008b) accelerated the senescence of stem and progenitor cells and inhibited angiogenesis (Dernbach et al, 2004). Tempol largely prevented the inhibition of proliferation of progenitor cells by high glucose concentrations (Zhang et al, 2008b).…”

Section: Major Organ Effects Of Tempolmentioning

confidence: 99%

“…Tempol largely prevented the inhibition of proliferation of progenitor cells by high glucose concentrations (Zhang et al, 2008b). Other studies have documented a pro-angiogenic action of tempol that may relate to a decrease in O 2 .- and thereby to increased NO bioactivity.…”

Section: Major Organ Effects Of Tempolmentioning

confidence: 99%

Effects of tempol and redox-cycling nitroxides in models of oxidative stress

Wilcox

2010

Pharmacology & Therapeutics

411

344

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Tempol is a redox cycling nitroxide that promotes the metabolism of many reactive oxygen species (ROS) and improves nitric oxide bioavailability. It has been studied extensively in animal models of oxidative stress. Tempol has been shown to preserve mitochondria against oxidative damage and improve tissue oxygenation. Tempol improved insulin responsiveness in models of diabetes mellitus and improved the dyslipidemia, reduced the weight gain and prevented diastolic dysfunction and heart failure in fat-fed models of the metabolic syndrome. Tempol protected many organs, including the heart and brain, from ischemia/reperfusion damage. Tempol prevented podocyte damage, glomerulosclerosis, proteinuria and progressive loss of renal function in models of salt and mineralocorticosteroid excess. It reduced brain or spinal cord damage after ischemia or trauma and exerted a spinal analgesic action. Tempol improved survival in several models of shock. It protected normal cells from radiation while maintaining radiation sensitivity of tumor cells. Its paradoxical pro-oxidant action in tumor cells accounted for a reduction in spontaneous tumor formation. Tempol was effective in some models of neurodegeneration. Thus, tempol has been effective in preventing several of the adverse consequences of oxidative stress and inflammation that underlie radiation damage and many of the diseases associated with aging. Indeed, tempol given from birth prolonged the life span of normal mice. However, presently tempol has been used only in human subjects as a topical agent to prevent radiation-induced alopecia.

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Biphasic response of endothelial progenitor cell proliferation induced by high glucose and its relationship with reactive oxygen species

Cited by 12 publications

References 18 publications

High Glucose Condition Induces Autophagy in Endothelial Progenitor Cells Contributing to Angiogenic Impairment

High Glucose Condition Induces Autophagy in Endothelial Progenitor Cells Contributing to Angiogenic Impairment

Hyperglycemia and Advanced Glycation End Products Regulate miR-126 Expression in Endothelial Progenitor Cells

Effects of tempol and redox-cycling nitroxides in models of oxidative stress

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