Trientine selectively delivers copper to the heart and suppresses pressure overload-induced cardiac hypertrophy in rats

Abstract

Dietary copper supplementation reverses pressure overload-induced cardiac hypertrophy by copper replenishment in the heart. A copper-selective chelator, trientine (triethylenetetramine [TETA]), reverses left ventricular hypertrophy associated with diabetes also by copper replenishment in the heart. The present study was undertaken to address the critical issue how TETA delivers copper to the heart. Adult male Sprague-Dawley rats were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Eight weeks after the TAC surgery, cardiac hypertrophy was developed and copper content in the heart was reduced. TETA was then administrated by gavage in two different dosages (21.9 or 87.6 mg/kg day) for six weeks. The results showed that in the lower dosage, TETA replenished copper contents in the heart, along with a decrease in the copper concentration in the blood and kidney, and an increase in the urine. In the higher dosage, TETA did not replenish copper contents in the heart, but markedly increased copper concentrations in the urine and decreased those in the blood and kidney. Neither lower nor higher TETA dosage altered copper concentrations in other organs. Corresponding to myocardial copper replenishment, the lower dose TETA suppresses cardiac hypertrophy, as judged by a reduction in the left ventricle wall thickness and a decrease in the heart size, and diminished cardiac fibrosis, as reflected by a decrease in collagen I content. TETA in the higher dose not only did not suppress cardiac hypertrophy, but also caused cardiac hypertrophy in sham-operated rats. TETA-mediated myocardial copper restoration is independent of copper transporter-1 or -2 but related to an energy-dependent transportation. This study demonstrates that low-dose TETA functions as a copper chaperone, selectively delivering copper to the copper-deprived heart through an active transportation; in higher doses, TETA simply retains its chelator function, removing copper from the body by urinary excretion. Impact statement Our study reveals that TETA, traditionally regarded as a copper chelator, in lower doses delivers copper selectively to the heart through a mechanism independent of copper transporter-1 or -2. Copper supplementation by a lower dose of TETA suppresses pressure overload-induced cardiac hypertrophy. Since ischemic heart disease and hypertrophic cardiomyopathy are accompanied by myocardial copper loss, this approach of using a lower dose of TETA to supplement copper to the heart would help treat the disease condition of patients with such cardiac events.

Expression of cardiac copper chaperone encoding genes and their correlation with cardiac function parameters in goats

“…Therefore, Cu exserts a potent cardiovascular health relevance because of its incorporation as a cofactor in antioxidant superoxide dismutase, lysyl oxidase, and mitochondrial cytochrome c-oxidase (Fukai et al 2018). Studies revealed that Cu de ciency (CuD) could be a leading cause of adverse cardiac events including ischemic and hypertrophic disorders (DiNicolantonio et al 2018, Li et al 2018, Liu et al 2018. Also, the alteration in the myocardial Cu acquisition mechanism was recently pointed out as the key factor in diabetes-induced heart failure in rats (Zhang et al 2020).…”

Copper promotion of myocardial regeneration

“…86 However, a recent study showed that TETA at a lower dosage (21.9 mg/kg day) actually selectively delivered copper to the copper-deficient hypertrophic hearts in rats. 21 Further studies revealed the possible mechanism by which TETA facilitates copper accumulation selectively in cardiomyocytes through the formation of Cu(II)-TETA complex that is transported to cardiomyocytes via an energy-dependent, but CTR1-independent, cross membrane transportation process in cardiomyocytes. 87…”

“…In the process of copper-induced angiogenesis, the fibrotic scar is also ameliorated, due to an increase of MMP-2 protein level and activity in the heart. 21 The coordination between angiogenesis and destruction of fibrotic scar guarantees a suitable microenvironment for myocardial regeneration.…”

“…16 However, copper is deprived in the ischemic myocardium. 14,17,18 Multiple approaches to increasing the availability of copper to the ischemic myocardium indeed reactivate the transactivation of HIF-1-regulated angiogenic genes, 19–21 leading to improved angiogenesis and promotion of myocardial regeneration.…”

The Molecular Mechanisms of Defective Copper Metabolism in Diabetic Cardiomyopathy

“…Many studies have shown that cardiac hypertrophy caused by pressure overload can be promoted by supplementing copper to promote the regression of cardiac hypertrophy [195][196][197]. However, for patients with diabetes and DCM, copper deficiency in cardiomyocytes is not due to insufficient dietary intake, but the inability of excess copper ions in blood to enter cells.…”