Abstract
Most patients with diabetes die from cardiac or arterial disease, for which there are limited therapeutic options. Free Cu2+ ions are strongly pro-oxidant, and chelatable-CuII is increased in the diabetic heart. We reported previously that treatment by CuII-selective chelation with triethylenetetramine (TETA) evokes elevated urinary CuII in diabetic rats and humans in whom it also improved hallmarks of established left ventricular (LV) disease. Here, we treated diabetic rats with TETA and evaluated its ability to ameliorate Cu2+-mediated LV and arterial damage by modifying the expression of molecular targets that included transforming growth factor (TGF)-β1, Smad4, extracellular matrix (ECM) proteins, extracellular superoxide dismutase (EC-SOD), and heparan sulfate (HS). Eight-weeks of TETA treatment significantly improved cardiac diastolic function but not [glucose]plasma in diabetic animals. LV and aortic mRNAs corresponding to TGF-β1, Smad4, collagen types I, III, and IV, and fibronectin-1, and plasminogen activator inhibitor-1, were elevated in untreated diabetic animals and normalized after TETA treatment. EC-SOD mRNA and protein, and [HS]tissue were significantly decreased in diabetes and restored by drug treatment. Candidate molecular mechanisms by which TETA could ameliorate diabetic cardiac and arteriovascular disease include the suppression of an activated TGF-β/Smad signaling pathway that mediates increased ECM gene expression and restoration of normal EC-SOD and HS regulation. These findings are relevant to the restoration toward normal by TETA treatment of cardiac and arterial structure and function in diabetes.
Footnotes
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This work was supported by grants from the Endocore Research Trust; the Foundation for Research Science and Technology, New Zealand; the New Zealand Ministry of Education through the Maurice Wilkins Centre for Molecular Biodiscovery; the Health Research Council of New Zealand; and by Protemix Corporation.
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The authors have all declared their association with Protemix Corporation, Auckland, New Zealand, and San Diego, California.
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ABBREVIATIONS: TETA, triethylenetetramine; ECM, extracellular matrix; EC-SOD, extracellular superoxide dismutase; HS, heparan sulfate; LV, left ventricle; NO, nitric oxide; , superoxide anion; PAI-1, plasminogen activator inhibitor-1; PCR, polymerase chain reaction; ROS, reactive oxygen species; STZ, streptozotocin; TGF-β1, transforming growth factor-β1.
- Received July 9, 2006.
- Accepted September 14, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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