Abstract 1742: Expression of the Anti-Angiogenic Proteins Angiostatin and Endostatin is Increased in Diabetic Patients and Associated with Impaired Coronary Collateral Formation
Introduction: Coronary artery disease is the leading cause of mortality in diabetics. Due to the diffuse nature of their disease, diabetics may be at risk for incomplete revascularization, highlighting a potential role for pro-angiogenic therapy in this group. This study investigates molecular mechanisms of angiogenesis in diabetics.
Methods: Myocardial tissue was harvested from patients undergoing CABG (non-diabetic (ND) 11, type 2 diabetic (DM) 10). Expression of angiostatin, endostatin, their precursors (plasminogen and collagen XVIII, respectively), enzymes leading to their production (Matrix Metalloprotease (MMP) 2 & 9), and an inhibitor of MMPs (TIMP2) was assessed with western blotting. MMP activity was assessed. Serum levels of angiostatin and endostatin were assayed. Coronary collateralization was graded by Rentrop scoring of angiograms.
Results: Plasminogen and collagen XVIII expression were similar between groups. Angiostatin expression trended to increase 1.24-fold (p=0.07) and endostatin expression increased 2.02-fold in DM patients relative to ND (p=0.02). Serum angiostatin was 2.68-fold higher (p=0.03) and endostatin 1.39-fold higher (p=0.04) in diabetics. MMP9 expression was no different between groups, whereas MMP2 expression decreased 1.8-fold in diabetics (p=0.003). MMP2 & 9 activity decreased 1.33-fold (p=0.03) and 1.57-fold (p=0.04), respectively, in diabetics. Coronary collateralization scores were ND 2.1 ± 0.37 vs. DM 1.0 ± 0.4 (p=0.05). Myocardial endostatin expression correlated strongly with %HbA1c (R=0.742, p=0.0001). Myocardial expression of angiostatin and endostatin demonstrated significant negative linear correlations with coronary collateralization (angiostatin R=−0.531, p=0.035, endostatin R=−0.794, p=0.0002).
Conclusion: Diabetics exhibit increased levels of the anti-angiogenic proteins angiostatin and endostatin and differential regulation of the enzymes governing their production relative to non-diabetics. Myocardial levels of these proteins show significant correlation to coronary collateralization. These findings offer potential new therapeutic targets for enhancing pro-angiogenic therapy and insight in to the angiogenic impairments seen in diabetes.