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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

05/12/2004

Pubmed ID

15136506

DOI

10.1161/01.CIR.0000129225.67353.1F

Scopus ID

2-s2.0-2442718997   67 Citations

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.

Author List

Weihrauch D, Lohr NL, Mraovic B, Ludwig LM, Chilian WM, Pagel PS, Warltier DC, Kersten JR

Authors

Nicole L. Lohr MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Paul S. Pagel MD, PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Angiogenesis Inducing Agents
Angiostatins
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
jenkins-FCD Prod-410 e9586552fe7f53c71f7923aa6e27aeabbd3c2473