Regeneration of the Heart in Diabetes by Selective Copper Chelation

Abstract

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 ␤ 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.

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

“…In study 2, rats (n=113) were assigned to one of six groups: (1) sham (n=23); (2) STZ (n=26); (3) STZ-TETA 20 mg/day per rat (n=23) [3][4][5]; (4) STZ-Def (ACROS, Geel, Belgium; 20 mg/day per rat, n=15) [11,12]; (5) STZPen (Sigma; St. Louis, MO, USA; 6 mg/day per rat, n=15) [2,8]; and (6) STZ-ZnA (Sigma; 0.5 mg day −1 rat −1 , n=11) [9,10]. A spot urine sample was collected from the bladder of each rat immediately before final tissue collection.…”

“…Isolated perfused working rat heart model Measurements of cardiac function were performed as previously described using this ex vivo approach [3,4] in hearts excised at week 16 from members of the following treatment groups: sham control; untreated diabetic; TETA-treated diabetic (20 mg/day per rat); Def-treated diabetic (20 mg/day per rat); Pentreated diabetic (6 mg/day per rat); and ZnA-treated diabetic (0.5 mg/day per rat). The numbers in each group are as shown in Electronic Supplementary Material (ESM) Table 1.…”

“…It is an orphan drug used in the treatment of the Wilson's disease [2] and has also shown beneficial effects in the experimental treatment of cardiac/vascular and renal disease in diabetes [3][4][5][6][7]. TETA treatment promotes urinary Cu(II) excretion in diabetic rats with streptozotocin (STZ)-induced diabetes and patients with type 2 diabetes, and restores cardiac structure and function in both [3,5].…”

“…Excessive accumulation of ECM proteins and associated myocardial fibrosis are implicated as pathogenic mechanisms in diabetic heart disease [28]. Increased fibrous ECM proteins provide the excess Cu-binding sites responsible for the accumulation of elevated loosely bound/chelatable Cu(II) in diabetes [1,3,29]. In a rat model of diabetic complications TETA treatment normalised cardiac and aortic fibrosis, and suppressed elevations of aortic and renal TGF-β1 production and urinary albumin/creatinine ratio (uACR) [3,4,30].…”

“…The numbers of rats assigned to each treatment were as stated below for the individual studies. Dosages of TETA were based on those found to be efficacious in diabetic rats and patients [1][2][3][4][5]. Dosages of Pen, Def and ZnA were equivalent to those reported to be efficacious in animals and patients, and drug dosing was verified by measurement of disappearance of the drinking water in all studies.…”