Dapagliflozin Restores Diabetes-Associated Decline in Vasculogenic Capacity of Endothelial Progenitor Cells via Activating AMPK-Mediated Inhibition of Inflammation and Oxidative Stress

2021 ◽  
Author(s):  
Lifang Luo ◽  
Bing Dong ◽  
Jianning Zhang ◽  
Yumin Qiu ◽  
Xiaolin Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Vascular Complications ◽  
Diabetic Patients ◽  
Vascular Protection ◽  
Endothelial Progenitor ◽  
Ampk Signaling ◽  
And Oxidative Stress

Abstract Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) provides added vascular protection beyond glucose lowering to patients with type 2 diabetes mellitus (T2DM). Endothelial progenitor cells (EPCs) are an important endogenous repair mechanism for diabetic vascular complications. Yet, whether SGLT2i protect vascular in diabetic patients by improving the function of EPCs remain to be elucidated. Methods: Sixty-three T2DM patients and 60 healthy participants were enrolled, and 15 of T2DM group taken dapagliflozin for 3 months. Retinal capillary density (RCD) and vasculogenic capacity of EPCs in vitro and in vivo were assessed among different groups. Genes related to inflammation/oxidative stress, and the AMPK signaling of EPCs in T2DM were determined before and after dapagliflozin treatment. Results: T2DM demonstrated a declined RCD and impaired vasculogenic capacity of EPCs. There is a linear correlation between RCD and the number of circulating EPCs. The expression of inflammation correlative genes was increased; however, anti-oxidative stress related genes expression was decreased in EPCs form T2DM, which were accompanied with reduced phosphorylation level of AMPK. Dapagliflozin treatment activated AMPK signaling, decreased the level of inflammation and oxidative stress, and rescued vasculogenic capacity of EPCs from T2DM. Furthermore, AMPK inhibitor pretreatment diminished the enhancement vasculogenic capacity of diabetic EPCs from dapagliflozin treatment.Conclusions: This study demonstrates for the first time that dapagliflozin restores vasculogenic capacity of EPCs via activating AMPK-mediated inhibition of inflammation and oxidative stress in T2DM.

Infusion of lin−/sca-1+ and endothelial progenitor cells improves proinflammatory and oxidative stress markers in atherosclerotic mice

2013 ◽  
Vol 167 (5) ◽  
pp. 1900-1905 ◽  
Author(s):  
Dimitris Tousoulis ◽  
Alexandros Briasoulis ◽  
Georgia Vogiatzi ◽  
Aggeliki Valatsou ◽  
Polina Kourkouti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Oxidative Stress Markers ◽  
Endothelial Progenitor ◽  
Stress Markers ◽  
And Oxidative Stress

Diabetes alters subsets of endothelial progenitor cells that reside in blood, bone marrow, and spleen

2012 ◽  
Vol 302 (6) ◽  
pp. C892-C901 ◽  
Author(s):  
Hidehito Saito ◽  
Yasuhiko Yamamoto ◽  
Hiroshi Yamamoto
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Insulin Treatment ◽  
Vascular Complications ◽  
Cell Number ◽  
Surface Marker ◽  
Endothelial Progenitor ◽  
Marker Combination

Circulating endothelial progenitor cells (EPCs) derived from the bone marrow (BM) participate in maintaining endothelial integrity and vascular homeostasis. Reduced EPC number and function result in vascular complications in diabetes. EPCs are a population of cells existing in various differentiation stages, and their cell surface marker profiles change during the process of mobilization and maturation. Hence, a generally accepted marker combination and a standardized protocol for the quantification of EPCs remain to be established. To determine the EPC subsets that are affected by diabetes, we comprehensively analyzed 32 surface marker combinations of mouse peripheral blood (PB), BM, and spleen cells by multicolor flow cytometry. Ten subsets equivalent to previously reported mouse EPCs significantly declined in number in the PB of streptozotocin-induced diabetic mice, and this reduction was reversed by insulin treatment. The PI−Lin−c-Kit−Sca-1+Flk-1−CD34−CD31+ EPC cluster, which can differentiate into mature endothelial cells in vitro, was the highest population in the PB, BM, and spleen and occurred 61 times more in the spleen than in the PB. The cell number significantly decreased in the BM as well as in the PB but paradoxically increased in the spleen under diabetic conditions. Insulin treatment reversed the decrease of EPC subsets in the BM and PB and reversed their increase in spleen. A similar tendency was observed in some of the major cell populations in db/db mice. To the best of our knowledge, we are the first to report spatial population changes in mouse EPCs by diabetes in the blood and in the BM across the spleen. Diminished circulating EPC supply by diabetes may be ascribed to impaired EPC production in the BM and to decreased EPC mobilization from the spleen, which may contribute to vascular dysfunction in diabetic conditions.

scholarly journals EFFECT OF FLAVONOIDS ON OXIDATIVE STRESS, APOPTOSIS, AND CELL MARKERS OF PERIPHERAL BLOOD-DERIVED ENDOTHELIAL PROGENITOR CELLS: AN IN VITRO STUDY

2021 ◽  
pp. 39-42
Author(s):  
WAHYU WIDOWATI ◽  
RIMONTA F. GUNANEGARA ◽  
TERESA LILIANA WARGASETIA ◽  
HANNA SARI WIDYA KUSUMA ◽  
SEILA ARUMWARDANA ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
In Vitro Study ◽  
Endothelial Progenitor ◽  
Peripheral Blood Mononuclear ◽  
Cell Markers

Objective: Circulating EPCs (endothelial progenitor cells) play a role in neovascularization and vascular repair. Oxidative stress impairs endothelial progenitor. Flavonoid is a phytochemical compound for antioxidant activity. Flavonoid effects toward oxidative stress, apoptosis, and expression of the cell markers on EPCs are not fully understood. This study was aimed to elucidate the effects of quercetin, kaempferol, and myricetin toward oxidative stress, apoptosis, and cell markers of peripheral blood-derived-EPCs. Methods: EPCs (endothelial progenitor cells) were isolated from peripheral blood mononuclear cells (PBMNCs) using cultivation under EPCs spesific media. Oxidative stress in EPCs was induced by H2O2 and then treated by quercetin, kaempferol, and myricetin. Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, while intracellular reactive oxygen species (ROS), apoptosis and characterization of cells, which expressed CD133 and KDR, was measured using flow cytometry. Results: Quercetin, kaempferol, and myricetin at concentration 12.50 µmol/l were not toxic on EPCs as the cells viability were 96.11±4.03%, 95.42±7.75%, and 94.22±9.49%, respectively. Flavonoids decreased intracellular ROS level in EPCs (quercetin: 14.38±1.47%, kaempferol: 20.21±6.25%, and myricetin: 13.88±4.02%) compared to EPCs treated with H2O2 (30.70%±1.04). Percetage of EPCs apoptosis was not significantly different among each treatment. Immunophenotyping showed the increasing of CD133 and KDR expression in EPCs treated with flavonoids. Conclusion: Quercetin, kaempferol, and myricetin were safe for EPCs, decreased ROS levels, and increased CD133 and KDR expression. However, the flavonoids did not significantly affect EPCs apoptosis.

scholarly journals Endothelial overexpression of metallothionein prevents diabetes mellitus-induced impairment in ischemia angiogenesis via preservation of HIF-1α/SDF-1/VEGF signaling in endothelial progenitor cells

2020 ◽  
Author(s):  
Ada Admin ◽  
Kai Wang ◽  
Xiaozhen Dai ◽  
Junhong He ◽  
Xiaoqing Yan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Flow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Mononuclear Cells ◽  
Tube Formation ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Endothelial Progenitor ◽  
Vegf Signaling

Diabetes-induced oxidative stress is one of the major contributors to dysfunction of endothelial progenitor cells (EPCs) and impaired endothelial regeneration. Thus, we tested whether increasing antioxidant protein metallothionein (MT) in EPCs promotes angiogenesis in a hind limb ischemia (HLI) model in endothelial MT transgenic (JTMT) mice with high fat diet and streptozocin-induced diabetes. Compared with littermate wild-type (WT) diabetic mice, JTMT diabetic mice had improved blood flow recovery and angiogenesis after HLI. Similarly, transplantation of JTMT bone marrow-derived mononuclear cells (BM-MNCs) stimulated greater blood flow recovery in <i>db/db</i> mice with HLI than did WT BM-MNCs. The improved recovery was associated with augmented EPC mobilization and angiogenic function. Further, cultured EPCs from diabetic patients exhibited decreased MT expression, increased cell apoptosis and impaired tube formation; while cultured JTMT-EPCs had enhanced cell survival, migration, and tube formation in hypoxia/hyperglycemic conditions compared with WT-EPCs. Mechanistically, MT overexpression enhanced hypoxia-inducible factor 1α (HIF-1α), stromal cell-derived factor (SDF-1) and vascular endothelial growth factor (VEGF) expression, and reduced oxidative stress in ischemic tissues. MT’s pro-EPC effects were abrogated by siRNA knockdown of HIF-1α without affecting MT’s anti-oxidant action. These results indicate that endothelial MT overexpression is sufficient to protect against diabetes-induced impairment of angiogenesis by promoting EPC functions most likely through upregulation of HIF-1α/SDF-1/VEGF signaling and reducing oxidative stress.

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