Active uptake of hydrophilic copper complex Cu(ii)-TETA in primary cultures of neonatal rat cardiomyocytes

Chunyan Fu, Junhong Lizhao, Zhenghui Luo, Tao Wang, Craig A. Grapperhaus, Xueqin Ding, Yujian Kang

Research output: Contribution to journalArticle

Abstract

Myocardial ischemia leads to copper efflux from the heart. The ischemic tissue with a low copper content fails to take up copper from the circulation even under the conditions of serum copper elevation. Cardiac copper repletion thus requires other available forms of this element than those currently known to bind to copper transport proteins. The copper complex of triethylenetetramine (TETA) is a metabolite of TETA, which has the potential to increase cardiac copper content in vivo. In the present study, we synthesized Cu(ii)-TETA, analyzed its crystal structure, and demonstrated the role of this compound in facilitating copper accumulation in primary cultures of neonatal rat cardiomyocytes. The Cu(ii)-TETA compound formed a square pyramidal chloride salt [Cu(TETA)Cl]Cl structure, which dissociates from chloride in aqueous solution to yield the four-coordinate dication Cu(ii)-TETA. Cu(ii)-TETA was accumulated as an intact compound in cardiomyocytes. Analysis from time-dependent copper accumulation in cardiomyocytes defined a different dynamic process in copper uptake between Cu(ii)-TETA and CuCl 2 exposure. An additive copper accumulation in cardiomyocytes was found when the cells were exposed to both CuCl 2 and Cu(ii)-TETA. Gene silencing of copper transport 1 (CTR1) did not affect cross-membrane transportation of Cu(ii)-TETA, but inhibited copper cellular accumulation from CuCl 2 . Furthermore, the uptake of Cu(ii)-TETA by cardiomyocytes was ATP-dependent. It is thus concluded that the formation of Cu(ii)-TETA facilitates copper accumulation in cardiomyocytes through an active CTR1-independent transportation process.

Original languageEnglish (US)
Pages (from-to)565-575
Number of pages11
JournalMetallomics
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2019

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Trientine
Cardiac Myocytes
Rats
Copper
Chlorides
Active Biological Transport
Adenosinetriphosphate

All Science Journal Classification (ASJC) codes

  • Chemistry (miscellaneous)
  • Biophysics
  • Biomaterials
  • Biochemistry
  • Metals and Alloys

Cite this

Active uptake of hydrophilic copper complex Cu(ii)-TETA in primary cultures of neonatal rat cardiomyocytes. / Fu, Chunyan; Lizhao, Junhong; Luo, Zhenghui; Wang, Tao; Grapperhaus, Craig A.; Ding, Xueqin; Kang, Yujian.

In: Metallomics, Vol. 11, No. 3, 01.03.2019, p. 565-575.

Research output: Contribution to journalArticle

Fu, Chunyan ; Lizhao, Junhong ; Luo, Zhenghui ; Wang, Tao ; Grapperhaus, Craig A. ; Ding, Xueqin ; Kang, Yujian. / Active uptake of hydrophilic copper complex Cu(ii)-TETA in primary cultures of neonatal rat cardiomyocytes. In: Metallomics. 2019 ; Vol. 11, No. 3. pp. 565-575.
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abstract = "Myocardial ischemia leads to copper efflux from the heart. The ischemic tissue with a low copper content fails to take up copper from the circulation even under the conditions of serum copper elevation. Cardiac copper repletion thus requires other available forms of this element than those currently known to bind to copper transport proteins. The copper complex of triethylenetetramine (TETA) is a metabolite of TETA, which has the potential to increase cardiac copper content in vivo. In the present study, we synthesized Cu(ii)-TETA, analyzed its crystal structure, and demonstrated the role of this compound in facilitating copper accumulation in primary cultures of neonatal rat cardiomyocytes. The Cu(ii)-TETA compound formed a square pyramidal chloride salt [Cu(TETA)Cl]Cl structure, which dissociates from chloride in aqueous solution to yield the four-coordinate dication Cu(ii)-TETA. Cu(ii)-TETA was accumulated as an intact compound in cardiomyocytes. Analysis from time-dependent copper accumulation in cardiomyocytes defined a different dynamic process in copper uptake between Cu(ii)-TETA and CuCl 2 exposure. An additive copper accumulation in cardiomyocytes was found when the cells were exposed to both CuCl 2 and Cu(ii)-TETA. Gene silencing of copper transport 1 (CTR1) did not affect cross-membrane transportation of Cu(ii)-TETA, but inhibited copper cellular accumulation from CuCl 2 . Furthermore, the uptake of Cu(ii)-TETA by cardiomyocytes was ATP-dependent. It is thus concluded that the formation of Cu(ii)-TETA facilitates copper accumulation in cardiomyocytes through an active CTR1-independent transportation process.",
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