Increased Antiangiogenic Protein Expression in the Skeletal Muscle of Diabetic Swine and Patients

Abstract

Antiangiogenic protein expression is increased in skeletal muscle in the setting of diabetes. In animal studies, diabetes was induced in 8 Yucatan miniswine via single alloxan injection at age 8 months, followed by skeletal muscle harvest 15 weeks later. Eight nondiabetic Yucatan miniswine served as controls. In patient studies, skeletal muscle was harvested from 11 nondiabetic patients and 10 patients with type 2 diabetes mellitus undergoing initial elective coronary artery bypass graft surgery. Skeletal muscle samples were analyzed via Western blotting and zymography for protein expression and enzyme activity. The study was performed in an academic medical center. Skeletal muscle expression of plasminogen, collagen XVIII, angiostatin, endostatin, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 2. Skeletal muscle expression of plasminogen and collagen XVIII (precursors of angiostatin and endostatin, respectively) remained similar between nondiabetic and diabetic swine and patients. Expression of angiostatin and endostatin was increased 1.70-fold and 1.84-fold, respectively, in diabetic swine relative to control swine. Endostatin expression was increased 1.69-fold in diabetic patients relative to nondiabetic patients. Matrix metalloproteinase 2 expression and activity were significantly increased in the skeletal muscle of diabetic swine and patients. Antiangiogenic protein levels are increased in the skeletal muscle in the setting of diabetes. Angiostatin, endostatin, and matrix metalloproteinases may offer novel therapeutic targets to improve collateral formation in patients with diabetes.