Oxidative Stress-Mediated Thrombospondin-2 Upregulation Impairs Bone Marrow-Derived Angiogenic Cell Function in Diabetes Mellitus

被引:48
|
作者
Bae, Ok-Nam [4 ,5 ]
Wang, Jie-Mei [1 ,2 ,3 ]
Baek, Seung-Hoon [4 ,6 ]
Wang, Qingde [1 ,2 ,3 ]
Yuan, Hong [1 ]
Chen, Alex F. [1 ,2 ,3 ]
机构
[1] Cent S Univ, Xiangya Hosp 3, Ctr Clin Pharmacol, Dept Cardiol, Changsha 410013, Hunan, Peoples R China
[2] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA
[3] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA
[4] Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA
[5] Hanyang Univ, Coll Pharm, Ansan, South Korea
[6] Ajou Univ, Coll Pharm, Suwon 441749, Gyeonggido, South Korea
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
angiogenesis inhibitors; diabetes; oxidative stress; stem cells; thrombospondin-2; human; ENDOTHELIAL PROGENITOR CELLS; MICRORNA EXPRESSION; PROLIFERATION; DISEASE; PATHOPHYSIOLOGY; PHENOTYPE; PROTECTS;
D O I
10.1161/ATVBAHA.113.301609
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective Circulating angiogenic cells play an essential role in angiogenesis but are dysfunctional in diabetes mellitus characterized by excessive oxidative stress. We hypothesize that oxidative stress-mediated upregulation of thrombospondin-2 (TSP-2), a potent antiangiogenic protein, contributes to diabetic bone marrow-derived angiogenic cell (BMAC) dysfunction. Approach and Results BMACs were isolated from adult male type 2 diabetic db/db mice and control db/+ (C57BLKS/J) mice. In Matrigel tube formation assay, angiogenic function was impaired in diabetic BMACs, accompanied by increased oxidative stress and nicotinamide adenine dinucleotide phosphate oxidase activity. BMAC angiogenic function was restored by overexpression of dominant negative Rac1 or by overexpression of manganese superoxide dismutase. TSP-2 mRNA and protein were both significantly upregulated in diabetic BMACs, mediated by increased oxidative stress as shown by a decrease in TSP-2 level after overexpression of dominant negative Rac1 or manganese superoxide dismutase. Silencing TSP-2 by its small interfering RNA in diabetic BMACs improved BMAC function in tube formation, adhesion, and migration assays. Notably, the upregulation of TSP-2 was also found in BMACs from streptozotocin-induced type 1 diabetic mice, and normal BMACs with high glucose treatment. let-7f, a microRNA which has been related to endothelial angiogenic function, is found to play key role in TSP-2 increase, but let-7f did not directly interact with TSP-2 mRNA. Conclusions The upregulation of TSP-2 mediated by increased oxidative stress contributes to angiogenesis dysfunction in diabetic BMACs.
引用
收藏
页码:1920 / 1927
页数:8
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