Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice

Marrotte, Eric J.; Chen, Dandan; Hakim, Jeffrey S.; Chen, Alex F.

doi:10.1172/jci36858

Cited by 174 publications

(222 citation statements)

References 42 publications

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“…As shown in Fig. 9, STZ-treated mice had impaired rate of wound healing compared to control mice, which is consistent with previous studies in STZ-induced model (15) and db/db mice (16). VEGF is known to accelerate wound healing, which is also confirmed by our data (Fig.…”

Section: Journal Of Biological Chemistry 409supporting

confidence: 93%

“…Then the skin was prepared with betadine and 70% ethanol (three times) and allowed to dry. A full thickness of 6-mm skin punch biopsy (Integra Miltex) was made as previously described (16). Treatments were applied directly on the wound bed in PBS at total volume of 5 l with or without recombinant human VEGF (200 ng) (37), ALLN (20 nmol), and PTP1B inhibitor (50 nmol, Calbiochem).…”

Section: Methodsmentioning

confidence: 99%

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Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells

Zhang

Youn

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangThe VEGF/VEGFR2/Akt/eNOS/NO pathway is essential to VEGF-induced angiogenesis. We have previously discovered a novel role of calpain in mediating VEGF-induced PI3K/AMPK/ Akt/eNOS activation through Ezrin. Here, we sought to identify possible feedback regulation of VEGFR2 by calpain via its substrate protein phosphotyrosine phosphatase 1B (PTP1B), and the relevance of this pathway to VEGF-induced angiogenesis, especially in diabetic wound healing. Overexpression of PTP1B inhibited VEGF-induced VEGFR2 and Akt phosphorylation in bovine aortic endothelial cells, while PTP1B siRNA increased both, implicating negative regulation of VEGFR2 by PTP1B. Calpain inhibitor ALLN induced VEGFR2 activation, which can be completely blocked by PTP1B overexpression. Calpain activation induced by overexpression or Ca/A23187 resulted in PTP1B cleavage, which can be blocked by ALLN. Moreover, calpain activation inhibited VEGF-induced VEGFR2 phosphorylation, which can be restored by PTP1B siRNA. These data implicate calpain/PTP1B negative feedback regulation of VEGFR2, in addition to the primary signaling pathway of VEGF/VEGFR2/ calpain/PI3K/AMPK/Akt/eNOS. We next examined a potential role of PTP1B in VEGF-induced angiogenesis. Endothelial cells transfected with PTP1B siRNA showed faster wound closure in response to VEGF. Aortic discs isolated from PTP1B siRNA-transfected mice also had augmented endothelial outgrowth. Importantly, PTP1B inhibition and/or calpain overexpression significantly accelerated wound healing in STZinduced diabetic mice. In conclusion, our data for the first time demonstrate a calpain/PTP1B/VEGFR2 negative feedback loop in the regulation of VEGF-induced angiogenesis. Modulation of local PTP1B and/or calpain activities may prove beneficial in the treatment of impaired wound healing in diabetes.

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Section: Journal Of Biological Chemistry 409supporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells

Zhang

Youn

et al. 2017

Journal of Biological Chemistry

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“…Increasing evidence from both clinical and laboratory studies indicate that innate immune cells can be programmed into diverse states with varying degrees of pro-and anti-inflammatory phenotypes (1,2), with consequences for host defense and inflammation (3). Despites its clinical relevance, mechanistic studies with regard to innate cell programming are scant.…”

mentioning

confidence: 99%

Dynamic Modulation of Innate Immune Response by Varying Dosages of Lipopolysaccharide (LPS) in Human Monocytic Cells

Morris

Gilliam

Button

et al. 2014

Journal of Biological Chemistry

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Background: Super-low-dose endotoxin causes mild but significant pro-inflammatory skewing. Results: Inhibition of GSK3 or activation of CREB ablates preferential induction of pro-inflammatory genes by super-low-dose LPS. Conclusion: GSK3 is necessary for pro-inflammatory gene induction in response to super-low-dose LPS, acting by activating FoxO1 and suppressing CREB. Significance: Persistent, non-resolving inflammation is a characteristic of many chronic diseases, and this study points toward potential therapeutic targets.

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“…A recent paper showed that reduced MnSOD activity may be critical in diabetic EPC dysfunction. 6) We investigated if mRNA level of MnSOD in EPCs is decreased under HG condition. The mRNA level of MnSOD was significantly reduced in HG-exposed EPCs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice

Cited by 174 publications

References 42 publications

Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells

Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells

Dynamic Modulation of Innate Immune Response by Varying Dosages of Lipopolysaccharide (LPS) in Human Monocytic Cells

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

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