Formation of STAT5/PPARγ Transcriptional Complex Modulates Angiogenic Cell Bioavailability in Diabetes

Dentelli, Patrizia; Trombetta, Antonella; Togliatto, Gabriele; Zeoli, Annarita; Rosso, Arturo; Uberti, Barbara; Orso, Francesca; Taverna, Daniela; Pegoraro, Luigi; Brizzi, Maria Felice

doi:10.1161/atvbaha.108.172247

Cited by 17 publications

(31 citation statements)

References 37 publications

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“…GATA2 directly binds to the VEGFR2 promoter and regulates its transcription, and the regulation is sensitive to extracellular matrix elasticity as well as soluble VEGF (7,12). STAT5 has been shown to modulate the endothelial cell and smooth muscle cell migration and proliferation, mediating FGF-induced angiogenesis (15,39,47,48). VEGF activates STAT5 through JAK2 phosphorylation, but how STAT5 regulates VEGFR2 is not determined (49,50).…”

Section: Discussionmentioning

confidence: 99%

GPR126 Protein Regulates Developmental and Pathological Angiogenesis through Modulation of VEGFR2 Receptor Signaling

Cui

Wang

Huang

et al. 2014

Journal of Biological Chemistry

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Background: GPR126 plays critical roles in development, but its function in vessels is not well characterized. Results: GPR126 regulates angiogenesis by modulating endothelial cell proliferation and migration via regulation of Vegfr2 expression. Conclusion: GPR126 is important for physiological and pathological angiogenesis. Significance: This finding provides a new functional mechanism for the regulation of angiogenesis.

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Section: Discussionmentioning

confidence: 99%

GPR126 Protein Regulates Developmental and Pathological Angiogenesis through Modulation of VEGFR2 Receptor Signaling

Cui

Wang

Huang

et al. 2014

Journal of Biological Chemistry

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“…Western blot Cells were lysed and 50 μg of protein was subjected to SDS-PAGE, and processed as described [33].…”

Section: Methodsmentioning

confidence: 99%

A diabetic milieu promotes OCT4 and NANOG production in human visceral-derived adipose stem cells

et al. 2012

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Aims/hypothesis Successful outcomes have been obtained by exploiting adipose-derived stem cells (ASCs) in regenerative medicine. NADPH oxidase (NOX)-generated reactive oxygen species (ROS) are known to control stem cell self-renewal. Several high glucose (HG)-mediated effects depend on NOX-generated ROS. In this study, we investigated whether, and how mechanistically, HG concentrations control ASC fate in patients with diabetes. Methods ASCs from the visceral adipose tissue of nondiabetic (N-ASCs) and diabetic participants (D-ASCs), identified by surface markers, were counted and evaluated for ROS generation and stem cell properties. Their ability to release soluble factors was assessed by BioPlex analysis. To reproduce an invitro diabetic glucose milieu, N-ASCs were cultured in HG (25 mmol/l) or normal glucose (NG) concentration (5 mmol/l), as control. ASC pluripotency was assessed by in vitro study. The p47 phox NOX subunit, AKT and octamer-binding transcription factor 4 (OCT4; also known as POU5F1) were knocked down by small-interfering RNA technology. Stem-cell features were evaluated by sphere cluster formation. Results The ASC number was higher in diabetic patients than in non-diabetic controls. Production of OCT4 and NANOG, stem-cell-specific transcription factors, was upregulated in D-ASCs compared with N-ASCs. Moreover, we found that ROS production and AKT activation drove D-ASC, but not N-ASC, secretion. When N-ASCs were cultured in vitro in the presence of HG, they also expressed OCT4/NANOG and formed spheres. By knock-down of the p47 phox NOX subunit, AKT and OCT4 we demonstrated that NOX-generated ROS and their downstream signals are crucial for HG-mediated ASC de-differentiation and proinflammatory cytokine production. Conclusions/interpretation We herein provide a rationale for exploiting D-ASCs in regenerative medicine and/or exploiting HG preconditioning to increase ASCs ex vivo.

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“…Cells were lysed and processed as previously described (34). H3K56 acetylation was evaluated on nuclear extracts from ECs.…”

Section: Western Blot Analysis and Nuclear Extractsmentioning

confidence: 99%

Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression

et al. 2014

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Reactive oxygen species (ROS) are crucial in longterm diabetes complications, including peripheral artery disease (PAD). In this study, we have investigated the potential clinical impact of unacylated ghrelin (UnAG) in a glucose intolerance and PAD mouse model. We demonstrate that UnAG is able to protect skeletal muscle and endothelial cells (ECs) from ROS imbalance in hind limb ischemiasubjected ob/ob mice. This effect translates into reductions in hind limb functional impairment. We show that UnAG rescues sirtuin 1 (SIRT1) activity and superoxide dismutase-2 (SOD-2) expression in ECs. This leads to SIRT1-mediated p53 and histone 3 lysate 56 deacetylation and results in reduced EC senescence in vivo. We demonstrate, using small interfering RNA technology, that SIRT1 is also crucial for SOD-2 expression. UnAG also renews micro-RNA (miR)-126 expression, resulting in the posttranscriptional regulation of vascular cell adhesion molecule 1 expression and a reduced number of infiltrating inflammatory cells in vivo. Loss-of-function experiments that target miR-126 demonstrate that miR-126 also controls SIRT1 and SOD-2 expression, thus confirming its role in driving UnAG-mediated EC protection against ROS imbalance. These results indicate that UnAG protects vessels from ROS imbalance in ob/ob mice by rescuing miR-126 expression, thus emphasizing its potential clinical impact in avoiding limb loss in PAD.

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Formation of STAT5/PPARγ Transcriptional Complex Modulates Angiogenic Cell Bioavailability in Diabetes

Cited by 17 publications

References 37 publications

GPR126 Protein Regulates Developmental and Pathological Angiogenesis through Modulation of VEGFR2 Receptor Signaling

GPR126 Protein Regulates Developmental and Pathological Angiogenesis through Modulation of VEGFR2 Receptor Signaling

A diabetic milieu promotes OCT4 and NANOG production in human visceral-derived adipose stem cells

Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression

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