Circulation Research. 2003;92:785-792
Published online before print March 6, 2003, doi: 10.1161/01.RES.0000065620.39919.20
Published online before print March 6, 2003, doi: 10.1161/01.RES.0000065620.39919.20
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© 2003 American Heart Association, Inc.
Integrative Physiology |
A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes
From the Division of Diabetes, Lipoproteins, and Metabolism (R.C., J.M.F., M.C.T., V.T., W.C.B., C.T., M.E.C., R.H.R.), Baker Heart Research Institute, Prahran, Victoria, Australia; the Department of Medicine, University of Melbourne, Austin and the Repatriation Medical Centre (R.G.D., M.E.C., L.M.B.), Heidelberg, Australia; and Diabetes Centre (S.M.T.), Royal Prince Alfred Hospital, Camperdown, Australia.
Correspondence to Prof Mark E. Cooper, Division of Diabetes, Lipoproteins and Metabolism, Baker Heart Research Institute, PO Box 6492 St Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail mark.cooper{at}baker.edu.au
The formation of advanced glycation end products (AGEs) on extracellular matrix components leads to accelerated increases in collagen cross linking that contributes to myocardial stiffness in diabetes. This study determined the effect of the crosslink breaker, ALT-711 on diabetes-induced cardiac disease. Streptozotocin diabetes was induced in Sprague-Dawley rats for 32 weeks. Treatment with ALT-711 (10 mg/kg) was initiated at week 16. Diabetic hearts were characterized by increased left ventricular (LV) mass and brain natriuretic peptide (BNP) expression, decreased LV collagen solubility, and increased collagen III gene and protein expression. Diabetic hearts had significant increases in AGEs and increased expression of the AGE receptors, RAGE and AGE-R3, in association with increases in gene and protein expression of connective tissue growth factor (CTGF). ALT-711 treatment restored LV collagen solubility and cardiac BNP in association with reduced cardiac AGE levels and abrogated the increase in RAGE, AGE-R3, CTGF, and collagen III expression. The present study suggests that AGEs play a central role in many of the alterations observed in the diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads to attenuation of diabetes-associated cardiac abnormalities in rats. This provides a potential new therapeutic approach for cardiovascular disease in human diabetes.
Key Words: diabetes mellitus • diabetic cardiomyopathy • advanced glycosylation end products • growth factors • crosslink breaker
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