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Molecular Changes Evoked by Triethylenetetramine Treatment in the Extracellular Matrix of the Heart and Aorta in Diabetic Rats

From the School of Biological Sciences (D.G., J.L., X.C., S.Y.C., S.Z., Y.-K.C., S.G.-J., A.R.J.P., G.J.S.C.), Faculty of Science, and the Maurice Wilkins Centre for Molecular Biodiscovery (S.Z., G.J.S.C.), University of Auckland, Auckland, New Zealand; and the Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (G.D.G., G.J.S.C.)

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-Cu^II is increased in the diabetic heart. We reported previously that treatment by Cu^II-selective chelation with triethylenetetramine (TETA) evokes elevated urinary Cu^II 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)-1, 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-1, 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-/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.

Address correspondence to: Dr. Garth J. S. Cooper, School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand., E-mail: g.cooper{at}auckland.ac.nz