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Angiostatin and Endostatin Expression Are Increased in the Skeletal Musculature of Diabetics
Neel R. Sodha1, Munir Boodhwani2, Richard T. Clements1, Shu-Hua Xu1, Sirisha Emani1, Cesario Bianchi1, Frank W. Sellke1
1Beth Israel Deaconess Medical Center / Harvard Medical School, Boston, MA;2University of Ottawa Heart Institute, Ottawa, ON, Canada

Objective:Diabetics can suffer from extensive peripheral-vascular-disease(PVD)/chronic lower extremity ischemia with diminished collateral formation manifesting clinically as impaired wound healing, claudication/rest-pain, and the subsequent need for revascularization or amputation. We hypothesized expression of anti-angiogenic proteins(Angiostatin and Endostatin), which are associated with impaired collateral vessel formation, is increased in diabetes.
Design:Animal Experimental Study/Comparative Patient Study
Setting:Academic Medical Center
Subjects:Yucatan-Miniswine: Non-Diabetic(ND,n=8), Diabetic(DM,n=8), Diabetic+Insulin-Therapy(DM+I,n=6) / Patients: Non-Diabetic(ND,n=11), Diabetic(DM,n=10)
Interventions:Yucatan-miniswine were separated into 3 groups with diabetes induced in 2 groups with Alloxan(ND/DM/DM+I) followed by tissue harvest after 8 weeks. Skeletal muscle was harvested from patients undergoing elective cardiac surgery.
Main Outcome Measures:Skeletal Muscle expression of Angiostatin, Endostatin, their precursors(Plasminogen/Collagen XVIII, respectively), the enzymes responsible for their production through cleavage(MMP-2/MMP-9), and an inhibitor of MMPs(TIMP-2).
Results:Plasminogen and Collagen XVIII expression remained similar between diabetic and non-diabetic swine and patients. DM-swine exhibited a 1.7-fold increase in angiostatin expression* and a 1.84-fold increase in endostatin expression*, whereas DM+I swine showed no significant difference in expression of either relative to ND-swine. Diabetic patients exhibited a 1.69-fold increase in endostatin expression* relative to non-diabetics. MMP-2 expression was increased 3.6-fold in DM-swine relative to ND-swine*, and returned to control(ND) levels with insulin therapy. No significant difference in MMP-2 expression between ND and DM patients was observed. *signifies p<0.05
Conclusions:Angiostatin and Endostatin expression is increased in the skeletal musculature of diabetics. Increased MMP-2 expression in diabetes may contribute to these increased levels. Angiostatin, Endostatin, and MMP-2 may represent key therapeutic targets to augment the angiogenic process in diabetics suffering from PVD.
Values expressed as densitometry units unless otherwise specified
Yucatan MiniswineMean FBS(mg/dL)PlasminogenCollagen XVIIIAngiostatinEndostatinMMP2MMP9TIMP2
ND73±5.963.7±17.333.7±17.350.0±12.429.9±2.94.6±1.663.5±12.124.2±4.8
DM262±23.470.5±12.940.5±12.986.0±7.555.0±8.616.5±4.683.5±6.556.2±9.7
DM+I138±17.353.7±7.139.7±7.159.2±9.037.7±7.03.7±1.461.2±9.334.7±5.9
PatientsHbA1c (%)PlasminogenCollagen XVIIIAngiostatinEndostatinMMP2MMP9TIMP2
ND5.65±0.1165.7±18.231.0±2.045.8±16.936.4±7.360.0±11.481.5±3.750.5±8.4
DM7.80±0.8653.2±13.931.8±3.771.0±15.061.5±9.435.3±8.766.0±6.147.8±7.4


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