Chronic hyperglycemia attenuates coronary collateral development and impairs proliferative properties of myocardial interstitial fluid by production of angiostatin. Circulation 2004 May 18;109(19):2343-8
Date
05/12/2004Pubmed ID
15136506DOI
10.1161/01.CIR.0000129225.67353.1FScopus ID
2-s2.0-2442718997 (requires institutional sign-in at Scopus site) 74 CitationsAbstract
BACKGROUND: Development of coronary collateral vessels is impaired in patients with diabetes mellitus. We tested the hypothesis that hyperglycemia alone attenuates collateral development and abolishes proliferative properties of myocardial interstitial fluid (MIF) by enhancing expression of matrix metalloproteinases (MMP) and angiostatin.
METHODS AND RESULTS: Chronically instrumented dogs were randomly assigned to receive an infusion of normal saline (control; n=9) or 70% dextrose in water to increase blood glucose to 350 to 400 mg/dL for 8 h/d (hyperglycemia; n=7) in the presence or absence (sham; n=9) of brief (2 minutes), repetitive coronary artery occlusions (1/h; 8/d for 21 days). Collateral perfusion increased to 41+/-11% and 49+/-6% of normal zone flow in control dogs on days 14 and 21 (P<0.05) but remained unchanged over 21 days in hyperglycemic and sham dogs (12+/-3% and 13+/-3%, respectively). A progressive reduction of the postocclusive peak reactive hyperemic response was also observed in control dogs (16+/-1 to 10+/-1 Hz. 10(2) on days 1 and 21, respectively) but not in hyperglycemic (17+/-2 to 20+/-2) or sham (17+/-2 to 16+/-1) dogs. Endothelial cell tube formation was produced by MIF obtained from control dogs but not hyperglycemic or sham dogs. Coincubation of MIF from hyperglycemic dogs with an angiostatin antibody restored endothelial cell tube formation. MMP-9 activity and expression of angiostatin were increased in dogs receiving exogenous glucose compared with controls
CONCLUSIONS: Chronic hyperglycemia abolishes development of coronary collateral vessels by increasing MMP-9 activity and angiostatin expression in dogs.
Author List
Weihrauch D, Lohr NL, Mraovic B, Ludwig LM, Chilian WM, Pagel PS, Warltier DC, Kersten JRAuthor
Dorothee Weihrauch DVM, PhD Research Scientist II in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Angiogenesis Inducing AgentsAngiostatins
Animals
Aorta
Body Fluids
Cell Division
Cells, Cultured
Collateral Circulation
Coronary Circulation
Coronary Disease
Disease Models, Animal
Dogs
Endothelial Cells
Endothelium, Vascular
Enzyme Induction
Glucose
Growth Substances
Humans
Hyperemia
Hyperglycemia
Matrix Metalloproteinase 9
Muscle, Smooth, Vascular
Myocardium
Myocytes, Smooth Muscle
Neovascularization, Physiologic
Plasminogen
Pulmonary Artery
Random Allocation
Rats