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

Author:

Biscetti Federico1,Straface Giuseppe2,De Cristofaro Raimondo3,Lancellotti Stefano3,Rizzo Paola1,Arena Vincenzo4,Stigliano Egidio4,Pecorini Giovanni1,Egashira Kensuke5,De Angelis Giulia6,Ghirlanda Giovanni1,Flex Andrea1

Affiliation:

1. Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy;

2. Vascular Medicine and Atherothrombosis Lab, Department of Experimental Medicine, Sapienza University of Rome, Polo Pontino, Italy;

3. Department of Internal Medicine, Haemostasis Research Center, Catholic University School of Medicine, Rome, Italy;

4. Department of Pathology, Catholic University School of Medicine, Rome, Italy;

5. Department of Cardiovascular Medicine, Kyushu University, Fukuoka, Japan; and

6. Department of Infectious Diseases, Catholic University School of Medicine, Rome, Italy.

Abstract

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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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