|
|
|
|
Back to NESS Scientific Program
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 Miniswine | Mean FBS(mg/dL) | Plasminogen | Collagen XVIII | Angiostatin | Endostatin | MMP2 | MMP9 | TIMP2 | | ND | 73±5.9 | 63.7±17.3 | 33.7±17.3 | 50.0±12.4 | 29.9±2.9 | 4.6±1.6 | 63.5±12.1 | 24.2±4.8 | | DM | 262±23.4 | 70.5±12.9 | 40.5±12.9 | 86.0±7.5 | 55.0±8.6 | 16.5±4.6 | 83.5±6.5 | 56.2±9.7 | | DM+I | 138±17.3 | 53.7±7.1 | 39.7±7.1 | 59.2±9.0 | 37.7±7.0 | 3.7±1.4 | 61.2±9.3 | 34.7±5.9 | | Patients | HbA1c (%) | Plasminogen | Collagen XVIII | Angiostatin | Endostatin | MMP2 | MMP9 | TIMP2 | | ND | 5.65±0.11 | 65.7±18.2 | 31.0±2.0 | 45.8±16.9 | 36.4±7.3 | 60.0±11.4 | 81.5±3.7 | 50.5±8.4 | | DM | 7.80±0.86 | 53.2±13.9 | 31.8±3.7 | 71.0±15.0 | 61.5±9.4 | 35.3±8.7 | 66.0±6.1 | 47.8±7.4 |
Back to NESS Scientific Program
|
