Chronic hyperglycemia attenuates coronary collateral development and impairs proliferative properties of myocardial interstitial fluid by production of angiostatin.

Abstract

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.

• Authors: Dorothee Weihrauch, Nicole L Lohr, Boris Mraovic, Lynda M Ludwig, William M Chilian, Paul S Pagel, David C Warltier, Judy R Kersten
• Journal: Circulation (Circulation) Vol. 109 Issue 19 Pg. 2343-8 (May 18 2004) ISSN: 1524-4539 [Electronic] United States
• PMID: 15136506 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiogenesis Inducing Agents
• Growth Substances
• Angiostatins
• Plasminogen
• Matrix Metalloproteinase 9
• Glucose

Topics

• Angiogenesis Inducing Agents (pharmacology)
• Angiostatins (biosynthesis, genetics)
• Animals
• Aorta
• Body Fluids (metabolism)
• Cell Division (drug effects)
• Cells, Cultured (cytology, drug effects)
• Collateral Circulation
• Coronary Circulation
• Coronary Disease (complications)
• Disease Models, Animal
• Dogs
• Endothelial Cells (cytology, drug effects)
• Endothelium, Vascular (cytology)
• Enzyme Induction (drug effects)
• Glucose (administration & dosage, toxicity)
• Growth Substances (pharmacology)
• Humans
• Hyperemia (etiology)
• Hyperglycemia (chemically induced, complications, metabolism, physiopathology)
• Matrix Metalloproteinase 9 (biosynthesis, genetics)
• Muscle, Smooth, Vascular (cytology)
• Myocardium (metabolism)
• Myocytes, Smooth Muscle (cytology, drug effects)
• Neovascularization, Physiologic (drug effects)
• Plasminogen (metabolism)
• Pulmonary Artery
• Random Allocation
• Rats