Liu Jiaming, Chen Chen, Liu Yinjie, Sun Xiaorong, Ding Xueqin, Qiu Liying, Han Pengfei, James Kang Y
Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Memphis Institute of Regenerative Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Exp Biol Med (Maywood). 2018 Oct;243(14):1141-1152. doi: 10.1177/1535370218813988. Epub 2018 Nov 24.
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.
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.
膳食补充铜通过补充心脏中的铜来逆转压力超负荷诱导的心脏肥大。一种铜选择性螯合剂，曲恩汀（三亚乙基四胺 [TETA]），也通过补充心脏中的铜来逆转与糖尿病相关的左心室肥大。本研究旨在解决曲恩汀如何将铜输送到心脏这一关键问题。成年雄性Sprague-Dawley大鼠接受横向主动脉缩窄（TAC）以诱导心脏肥大。TAC手术后8周，心脏肥大形成，心脏中的铜含量降低。然后以两种不同剂量（21.9或87.6毫克/千克·天）通过灌胃给予曲恩汀，持续6周。结果表明，低剂量时，曲恩汀补充了心脏中的铜含量，同时血液和肾脏中的铜浓度降低，尿液中的铜浓度升高。高剂量时，曲恩汀没有补充心脏中的铜含量，但显著增加了尿液中的铜浓度，并降低了血液和肾脏中的铜浓度。低剂量和高剂量的曲恩汀均未改变其他器官中的铜浓度。与心肌铜补充相对应，低剂量曲恩汀可抑制心脏肥大，这可通过左心室壁厚度的减少和心脏大小的减小来判断，并且可减少心肌纤维化，这可通过I型胶原蛋白含量的降低来反映。高剂量的曲恩汀不仅没有抑制心脏肥大，反而在假手术大鼠中导致了心脏肥大。曲恩汀介导的心肌铜恢复与铜转运蛋白-1或-2无关，但与能量依赖性转运有关。本研究表明，低剂量的曲恩汀起铜伴侣的作用，通过主动转运将铜选择性地输送到缺铜的心脏；高剂量时，曲恩汀仅保留其螯合剂功能，通过尿液排泄从体内清除铜。
我们的研究表明，传统上被视为铜螯合剂的曲恩汀，低剂量时通过一种独立于铜转运蛋白-1或-2的机制将铜选择性地输送到心脏。低剂量曲恩汀补充铜可抑制压力超负荷诱导的心脏肥大。由于缺血性心脏病和肥厚性心肌病伴有心肌铜丢失，这种使用低剂量曲恩汀向心脏补充铜的方法将有助于治疗患有此类心脏疾病的患者的病情。
