Copper(II)-selective chelation improves function and antioxidant defences in cardiovascular tissues of rats as a model of diabetes: comparisons between triethylenetetramine and three less copper-selective transition-metal-targeted treatments.
OBJECTIVE
Treatment with the Cu(II)-selective chelator triethylenetetramine (TETA) improves cardiovascular disease in human patients, and cardiac and vascular/renal disease in rats used as a model of diabetes. Here we tested two hypotheses: first, that TETA elicits greater improvement in organ function than less Cu-selective transition-metal-targeted treatments; second, that the therapeutic actions of TETA are consistent with mediation through suppression of oxidative stress.


METHODS
Rats were made diabetic with streptozotocin (55 mg/kg, i. v.) and treated from 8 weeks after disease induction for the following 8 weeks with effective dosages of oral TETA, or one of three less Cu-selective transition-metal-targeted treatments: D-penicillamine, deferiprone or Zn acetate. Treatment effects were measured in ex vivo cardiac and aortic tissues, plasma and urine.


RESULTS
Diabetes damaged both cardiac and renal/vascular function by impairing the ability of cardiac output to respond physiologically to rising afterload, and by significantly elevating the urinary albumin/creatinine ratio. Diabetes also lowered total antioxidant potential and heparan sulphate levels in cardiac and arterial tissues, and serum ferroxidase activity, whereas it elevated urinary heparan sulphate excretion. TETA treatment rectified or partially rectified all these defects, whereas the other three experimental treatments were ineffectual. By contrast, none of the four drug treatments lowered diabetes-mediated elevations of plasma glucose or lipid concentrations.


CONCLUSIONS
TETA may limit the cardiac and renal/vascular damage inflicted by diabetes through its actions to reinforce antioxidant defence mechanisms, probably acting through selective chelation of 'loosely-bound'/chelatable Cu(II). It may also improve heparan sulphate homeostasis and bolster antioxidant defence by increasing vascular extracellular superoxide dismutase activity. Urinary albumin/creatinine ratio might prove useful for monitoring TETA treatment.
Lu
J
J
School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag, 92019 Auckland, New Zealand.
Gong
D
D
Choong
S Y
SY
Xu
H
H
Chan
Y-K
YK
Chen
X
X
Fitzpatrick
S
S
Glyn-Jones
S
S
Zhang
S
S
Nakamura
T
T
Ruggiero
K
K
Obolonkin
V
V
Poppitt
S D
SD
Phillips
A R J
AR
Cooper
G J S
GJ
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002614:Chelating Agents / Q000627:therapeutic use; D000077543:Deferiprone; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000652:urine; D006321:Heart / Q000187:drug effects*; D006497:Heparan Sulfate / Q000652:urine; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects*; D010396:Penicillamine / Q000627:therapeutic use; D011728:Pyridones / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D014266:Trientine / Q000627:therapeutic use*; D019345:Zinc Acetate / Q000627:therapeutic use
D002614:Chelating Agents; D000077543:Deferiprone; D006497:Heparan Sulfate; D010396:Penicillamine; D011728:Pyridones; D014266:Trientine; D019345:Zinc Acetate