title: Molecular changes evoked by triethylenetetramine treatment in the extracellular matrix of the heart and aorta in diabetic rats.
abstract: Most patients with diabetes die from cardiac or arterial disease, for which there are limited therapeutic options. Free Cu(2+) 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 Cu(2+)-mediated LV and arterial damage by modifying the expression of molecular targets that included transforming growth factor (TGF)-beta1, 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-beta1, 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-beta/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.
authors.affiliation: School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Deming
authors.initials: D
authors.lastname: Gong
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Xiuyin
authors.initials: X
authors.lastname: Chen
authors.forename: Soon Y
authors.initials: SY
authors.lastname: Choong
authors.forename: Shaoping
authors.initials: S
authors.lastname: Zhang
authors.forename: Yih-Kai
authors.initials: YK
authors.lastname: Chan
authors.forename: Sarah
authors.initials: S
authors.lastname: Glyn-Jones
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Gamble
authors.forename: Anthony R J
authors.initials: AR
authors.lastname: Phillips
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D001483:Base Sequence; D015153:Blotting, Western; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D017931:DNA Primers; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D013481:Superoxides; D003300:Copper; D013482:Superoxide Dismutase