Received for publication July 10, 2006.
Revised September 13, 2006.
Accepted for publication September 14, 2006.

Molecular Changes Evoked by Triethylenetetramine (TETA) Treatment in the Extracelluar Matrix of the Heart and Aorta in Diabetic Rats

Abstract

Most diabetic subjects 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 previously reported 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 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-week's 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 (PAI-1), were elevated in untreated diabetic animals and normalized following 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 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 towards normal by TETA treatment of cardiac and arterial structure and function in diabetes.

Key words: Molecular dynamics, Metals and chelators, Oxidative stress/antioxidants