Regeneration of the heart in diabetes by selective copper chelation.
Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.
Cooper
Garth J S
GJ
Level 4, Thomas Building, School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. g.cooper@auckland.ac.nz
Phillips
Anthony R J
AR
Choong
Soon Y
SY
Leonard
Bridget L
BL
Crossman
David J
DJ
Brunton
Dianne H
DH
Saafi
'Etuate L
'L
Dissanayake
Ajith M
AM
Cowan
Brett R
BR
Young
Alistair A
AA
Occleshaw
Christopher J
CJ
Chan
Yih-Kai
YK
Leahy
Fiona E
FE
Keogh
Geraldine F
GF
Gamble
Gregory D
GD
Allen
Grant R
GR
Pope
Adèle J
AJ
Boyd
Peter D W
PD
Poppitt
Sally D
SD
Borg
Thomas K
TK
Doughty
Robert N
RN
Baker
John R
JR
D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000652:urine*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration / Q000187:drug effects; D014266:Trientine / Q000494:pharmacology*
D002614:Chelating Agents; D003300:Copper; D014266:Trientine