title: Endostatin and angiostatin are increased in diabetic patients with coronary artery disease and associated with impaired coronary collateral formation.
abstract: Coronary artery disease (CAD) is the leading cause of mortality in diabetic patients. Because of the diffuse nature of their disease, diabetic patients may be at risk for incomplete revascularization, highlighting a potential role for proangiogenic therapy in this group. This study investigates molecular mechanisms of angiogenesis in diabetic patients. Myocardial tissue was harvested from patients undergoing coronary artery bypass grafting [nondiabetic (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 and -9, cathepsin L], and an inhibitor of MMPs (tissue inhibitor of metalloproteinase) was assessed with Western blotting. MMP activity was assessed. Coronary collateralization was graded by Rentrop scoring of angiograms. 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). MMP-9 expression was no different between groups, whereas MMP-2 expression decreased 1.8-fold in diabetics (P = 0.003). MMP-2 and -9 activity decreased 1.33-fold (P = 0.03) and 1.57-fold (P = 0.04), respectively, in diabetic patients. Cathepsin L expression was 1.38-fold higher in diabetic patients (P = 0.02). Coronary collateralization scores were ND 2.1 +/- 0.37 vs. DM 1.0 +/- 0.4 (P = 0.05). Myocardial endostatin expression correlated strongly with the percentage of hemoglobin A(1c) (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). Diabetic patients with CAD exhibit increased levels of the antiangiogenic proteins angiostatin and endostatin and differential regulation of the enzymes governing their production relative to ND patients. Myocardial levels of these proteins show significant correlation to coronary collateralization. These findings offer potential new therapeutic targets for enhancing proangiogenic therapy and insight into the angiogenic impairments seen in diabetes.
authors.affiliation: Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Neel R
authors.initials: NR
authors.lastname: Sodha
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.forename: Munir
authors.initials: M
authors.lastname: Boodhwani
authors.forename: Shu-Hua
authors.initials: SH
authors.lastname: Xu
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Laham
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000368:Aged; D043168:Angiostatins / Q000032:analysis*; D056668:Cathepsin L; D002403:Cathepsins / Q000032:analysis; D043170:Collagen Type XVIII / Q000032:analysis; D003097:Collateral Circulation; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D003326:Coronary Circulation; D003546:Cysteine Endopeptidases / Q000032:analysis; D048909:Diabetes Complications / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D043169:Endostatins / Q000032:analysis*; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D016014:Linear Models; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D009206:Myocardium / Q000737:chemistry* / Q000201:enzymology; D010958:Plasminogen / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis
chemical_list: D043168:Angiostatins; D056668:Cathepsin L; D002403:Cathepsins; D043170:Collagen Type XVIII; D003546:Cysteine Endopeptidases; D043169:Endostatins; D006442:Glycated Hemoglobin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010958:Plasminogen; D019716:Tissue Inhibitor of Metalloproteinase-2; C517652:hemoglobin A1c protein, human; C534281:CTSL protein, human; C522361:MMP2 protein, human