Upregulated copper transporters in hypoxia-induced pulmonary hypertension

Adriana M. Zimnicka, Haiyang Tang, Qiang Guo, Frank K. Kuhr, Myung Jin Oh, Jun Wan, Jiwang Chen, Kimberly A. Smith, Dustin R. Fraidenburg, Moumita S.R. Choudhury, Irena Levitan, Roberto Machado, Jack H. Kaplan, Jason X.J. Yuan

Research output: Contribution to journalArticle

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Abstract

Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness.

Original languageEnglish (US)
Article numbere90544
JournalPLoS One
Volume9
Issue number3
DOIs
StatePublished - Mar 10 2014
Externally publishedYes

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Protein-Lysine 6-Oxidase
Pulmonary Hypertension
hypertension
transporters
Muscle
hypoxia
Copper
copper
lungs
Lung
Smooth Muscle Myocytes
Animals
Extracellular Matrix
Cells
Stiffness
Vascular Stiffness
smooth muscle
myocytes
Hypoxia-Inducible Factor 1
Elastin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Zimnicka, A. M., Tang, H., Guo, Q., Kuhr, F. K., Oh, M. J., Wan, J., ... Yuan, J. X. J. (2014). Upregulated copper transporters in hypoxia-induced pulmonary hypertension. PLoS One, 9(3), [e90544]. https://doi.org/10.1371/journal.pone.0090544

Upregulated copper transporters in hypoxia-induced pulmonary hypertension. / Zimnicka, Adriana M.; Tang, Haiyang; Guo, Qiang; Kuhr, Frank K.; Oh, Myung Jin; Wan, Jun; Chen, Jiwang; Smith, Kimberly A.; Fraidenburg, Dustin R.; Choudhury, Moumita S.R.; Levitan, Irena; Machado, Roberto; Kaplan, Jack H.; Yuan, Jason X.J.

In: PLoS One, Vol. 9, No. 3, e90544, 10.03.2014.

Research output: Contribution to journalArticle

Zimnicka, AM, Tang, H, Guo, Q, Kuhr, FK, Oh, MJ, Wan, J, Chen, J, Smith, KA, Fraidenburg, DR, Choudhury, MSR, Levitan, I, Machado, R, Kaplan, JH & Yuan, JXJ 2014, 'Upregulated copper transporters in hypoxia-induced pulmonary hypertension', PLoS One, vol. 9, no. 3, e90544. https://doi.org/10.1371/journal.pone.0090544
Zimnicka AM, Tang H, Guo Q, Kuhr FK, Oh MJ, Wan J et al. Upregulated copper transporters in hypoxia-induced pulmonary hypertension. PLoS One. 2014 Mar 10;9(3). e90544. https://doi.org/10.1371/journal.pone.0090544
Zimnicka, Adriana M. ; Tang, Haiyang ; Guo, Qiang ; Kuhr, Frank K. ; Oh, Myung Jin ; Wan, Jun ; Chen, Jiwang ; Smith, Kimberly A. ; Fraidenburg, Dustin R. ; Choudhury, Moumita S.R. ; Levitan, Irena ; Machado, Roberto ; Kaplan, Jack H. ; Yuan, Jason X.J. / Upregulated copper transporters in hypoxia-induced pulmonary hypertension. In: PLoS One. 2014 ; Vol. 9, No. 3.
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AU - Chen, Jiwang

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