TY - JOUR
T1 - Molecular changes evoked by triethylenetetramine treatment in the extracellular matrix of the heart and aorta in diabetic rats
AU - Gong, Deming
AU - Lu, Jun
AU - Chen, Xiuyin
AU - Choong, Soon Y.
AU - Zhang, Shaoping
AU - Chan, Yih Kai
AU - Glyn-Jones, Sarah
AU - Gamble, Gregory D.
AU - Phillips, Anthony R J
AU - Cooper, Garth
PY - 2006
Y1 - 2006
N2 - 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. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.
AB - 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. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.
U2 - 10.1124/mol.106.028605
DO - 10.1124/mol.106.028605
M3 - Article
C2 - 16973718
SN - 1521-0111
VL - 70
SP - 2045
EP - 2051
JO - Molecular pharmacology
JF - Molecular pharmacology
IS - 6
ER -
