High-Mobility Group Box-1 Protein Promotes Angiogenesis After Peripheral Ischemia in Diabetic Mice Through a VEGF-Dependent Mechanism

被引:114
作者
Biscetti, Federico [1 ]
Straface, Giuseppe [2 ]
De Cristofaro, Raimondo [3 ]
Lancellotti, Stefano [3 ]
Rizzo, Paola [1 ]
Arena, Vincenzo [4 ]
Stigliano, Egidio [4 ]
Pecorini, Giovanni [1 ]
Egashira, Kensuke [5 ]
De Angelis, Giulia [6 ]
Ghirlanda, Giovanni [1 ]
Flex, Andrea [1 ]
机构
[1] Univ Cattolica Sacro Cuore, Sch Med, Lab Vasc Biol & Genet, Dept Med,A Gemelli Univ Hosp, Rome, Italy
[2] Univ Roma La Sapienza, Dept Expt Med, Vasc Med & Atherothrombosis Lab, Polo Pontino, Italy
[3] Univ Cattolica Sacro Cuore, Sch Med, Haemostasis Res Ctr, Dept Internal Med, Rome, Italy
[4] Univ Cattolica Sacro Cuore, Sch Med, Dept Pathol, Rome, Italy
[5] Kyushu Univ, Dept Cardiovasc Med, Fukuoka 812, Japan
[6] Univ Cattolica Sacro Cuore, Sch Med, Dept Infect Dis, Rome, Italy
关键词
ENDOTHELIAL GROWTH-FACTOR; END-PRODUCTS RAGE; TISSUE-DAMAGE; RAT MODEL; RECEPTOR; HMGB1; DYSFUNCTION; HINDLIMB; CELLS; FLT-1;
D O I
10.2337/db09-1507
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
OBJECTIVE-High-mobility group box-1 (HMGB1) protein is a nuclear DNA-binding protein released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. Diabetic human and mouse tissues contain lower levels of HMGB1 than their normoglycemic counterparts. Deficient angiogenesis after ischemia contributes to worse outcomes of peripheral arterial disease in patients with diabetes. To test the hypothesis that HMGB1 enhances ischemia-induced angiogenesis in diabetes, we administered HMGB1 protein in a mouse hind limb ischemia model using diabetic mice. RESEARCH DESIGN AND METHODS-After the induction of diabetes by streptozotocin, we studied ischemia-induced neovascularization in the ischemic hind limb of normoglycemic, diabetic, and HMGB1-treated diabetic mice. RESULTS-We found that the perfusion recovery was significantly attenuated in diabetic mice compared with normoglycemic control mice. Interestingly, HMGB1 protein expression was lower in the ischemic tissue of diabetic mice than in normoglycemic mice. Furthermore, we observed that HMGB1 administration restored the blood flow recovery and capillary density in the ischemic muscle of diabetic mice, that this process was associated with the increased expression of vascular endothelial growth factor (VEGF), and that HMGB1-induced angiogenesis was significantly reduced by inhibiting VEGF activity. CONCLUSIONS-The results of this study show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent mechanism. Diabetes 59:1496-1505, 2010
引用
收藏
页码:1496 / 1505
页数:10
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