Increased antiangiogenic protein expression in the skeletal muscle of diabetic swine and patients.
OBJECTIVE
Antiangiogenic protein expression is increased in skeletal muscle in the setting of diabetes.


METHODS
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.


METHODS
Skeletal muscle expression of plasminogen, collagen XVIII, angiostatin, endostatin, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 2.


RESULTS
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.


CONCLUSIONS
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.
Sodha
Neel R
NR
Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Boodhwani
Munir
M
Clements
Richard T
RT
Xu
Shu-Hua
SH
Khabbaz
Kamal R
KR
Sellke
Frank W
FW
D000368:Aged; D043168:Angiostatins / Q000378:metabolism*; D000818:Animals; D016022:Case-Control Studies; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D043169:Endostatins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D013552:Swine; D013556:Swine, Miniature
D043169:Endostatins; D043168:Angiostatins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9