This Article Full Text Full Text (PDF) All Versions of this Article: 109/19/2343    most recent 01.CIR.0000129225.67353.1Fv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weihrauch, D. Articles by Kersten, J. R. Search for Related Content PubMed PubMed Citation Articles by Weihrauch, D. Articles by Kersten, J. R. Related Collections Angiogenesis Type 2 diabetes Other diabetes Coronary circulation

(Circulation. 2004;109:2343-2348.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Chronic Hyperglycemia Attenuates Coronary Collateral Development and Impairs Proliferative Properties of Myocardial Interstitial Fluid by Production of Angiostatin

Dorothee Weihrauch, DVM, PhD; Nicole L. Lohr, BS; Boris Mraovic, MD; Lynda M. Ludwig, BS; William M. Chilian, PhD; Paul S. Pagel, MD, PhD; David C. Warltier, MD, PhD; Judy R. Kersten, MD

From the Cardiovascular Research Center (D.C.W., J.R.K.) and the Departments of Anesthesiology (D.C.W., N.L.L., B.M., L.M.L., P.S.P., D.C.W., J.R.K.), Pharmacology and Toxicology (L.M.L., D.C.W., J.R.K.), and Medicine (Division of Cardiovascular Diseases) (D.C.W.), Medical College of Wisconsin, Milwaukee; the Clement J. Zablocki Veterans Affairs Medical Center (P.S.P., D.C.W.), Milwaukee, Wis; and the Department of Physiology (W.M.C.), Health Science Center, Louisiana State University, New Orleans.

Correspondence to Judy R. Kersten, MD, Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail jkersten{at}mcw.edu

Received December 17, 2003; revision received January 28, 2004; accepted February 2, 2004.

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 · 10² 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.

Key Words: angiogenesis • collateral circulation • diabetes mellitus • glucose • metalloproteinases

This article has been cited by other articles:

				N. Labinskyy, P. Mukhopadhyay, J. Toth, G. Szalai, M. Veres, G. Losonczy, J. T. Pinto, P. Pacher, P. Ballabh, A. Podlutsky, et al. Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H946 - H956. [Abstract] [Full Text] [PDF]

				N. R. Sodha, R. T. Clements, M. Boodhwani, S.-H. Xu, R. J. Laham, C. Bianchi, and F. W. Sellke Endostatin and angiostatin are increased in diabetic patients with coronary artery disease and associated with impaired coronary collateral formation Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H428 - H434. [Abstract] [Full Text] [PDF]

				N. R. Sodha, M. Boodhwani, R. T. Clements, S.-H. Xu, K. R. Khabbaz, and F. W. Sellke Increased Antiangiogenic Protein Expression in the Skeletal Muscle of Diabetic Swine and Patients Arch Surg, May 1, 2008; 143(5): 463 - 470. [Abstract] [Full Text] [PDF]

				G. Spinetti, N. Kraenkel, C. Emanueli, and P. Madeddu Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies Cardiovasc Res, May 1, 2008; 78(2): 265 - 273. [Abstract] [Full Text] [PDF]

				M. Boodhwani, N. R. Sodha, S. Mieno, B. Ramlawi, S.-H. Xu, J. Feng, R. T. Clements, M. Ruel, and F. W. Sellke Insulin treatment enhances the myocardial angiogenic response in diabetes. J. Thorac. Cardiovasc. Surg., December 1, 2007; 134(6): 1453 - 1460. [Abstract] [Full Text] [PDF]

				M. Boodhwani, N. R. Sodha, S. Mieno, S.-H. Xu, J. Feng, B. Ramlawi, R. T. Clements, and F. W. Sellke Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Chronic Myocardial Ischemia in Diabetes Circulation, September 11, 2007; 116(11_suppl): I-31 - I-37. [Abstract] [Full Text] [PDF]

				D. Weihrauch, H. Xu, Y. Shi, J. Wang, J. Brien, D. W. Jones, S. Kaul, R. A. Komorowski, M. E. Csuka, K. T. Oldham, et al. Effects of D-4F on vasodilation, oxidative stress, angiostatin, myocardial inflammation, and angiogenic potential in tight-skin mice Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1432 - H1441. [Abstract] [Full Text] [PDF]

				A. W.Y. Chung, Y. N. Hsiang, L. A. Matzke, B. M. McManus, C. van Breemen, and E. B. Okon Reduced Expression of Vascular Endothelial Growth Factor Paralleled With the Increased Angiostatin Expression Resulting From the Upregulated Activities of Matrix Metalloproteinase-2 and -9 in Human Type 2 Diabetic Arterial Vasculature Circ. Res., July 21, 2006; 99(2): 140 - 148. [Abstract] [Full Text] [PDF]

				Y. Naka and D. Belov Invited commentary Ann. Thorac. Surg., February 1, 2006; 81(2): 642 - 642. [Full Text] [PDF]

				J. J. M. Greer, D. P. Ware, and D. J. Lefer Myocardial infarction and heart failure in the db/db diabetic mouse Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H146 - H153. [Abstract] [Full Text] [PDF]

				M. Simons Angiogenesis, Arteriogenesis, and Diabetes: Paradigm Reassessed? J. Am. Coll. Cardiol., September 6, 2005; 46(5): 835 - 837. [Full Text] [PDF]

				Highlights from the Literature Physiology, August 1, 2004; 19(4): 161 - 167. [Full Text] [PDF]