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Upregulated copper transporters in hypoxia-induced pulmonary hypertension
- Source :
- PLoS ONE, PLoS ONE, Vol 9, Iss 3, p e90544 (2014)
- Publication Year :
- 2013
-
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.
- Subjects :
- Male
Pathology
Vascular smooth muscle
lcsh:Medicine
Gene Expression
Apoptosis
030204 cardiovascular system & hematology
Cardiovascular
Biochemistry
Protein-Lysine 6-Oxidase
0302 clinical medicine
Cell Movement
Molecular Cell Biology
Morphogenesis
Signaling in Cellular Processes
RNA, Small Interfering
lcsh:Science
Hypoxia
Cation Transport Proteins
Lung
Chelating Agents
0303 health sciences
Multidisciplinary
biology
Cobalt
3. Good health
Up-Regulation
Extracellular Matrix
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
Gene Knockdown Techniques
Cytochemistry
Medicine
medicine.symptom
Research Article
Signal Transduction
medicine.medical_specialty
Hypertension, Pulmonary
ATP7A
Myocytes, Smooth Muscle
Down-Regulation
Lysyl oxidase
Cell Migration
Pulmonary Artery
Extracellular Matrix Signaling
Cell Growth
Molecular Genetics
03 medical and health sciences
Internal medicine
Proliferating Cell Nuclear Antigen
medicine
Genetics
Animals
Humans
Pulmonary Vascular Diseases
RNA, Messenger
Biology
030304 developmental biology
Cell Proliferation
business.industry
lcsh:R
Computational Biology
Hypoxia (medical)
medicine.disease
Hypoxia-Inducible Factor 1, alpha Subunit
Pulmonary hypertension
Mice, Inbred C57BL
Endocrinology
Vascular resistance
biology.protein
lcsh:Q
business
Elastin
Copper
Developmental Biology
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 9
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....718941b38ef73340d0d7788c82ca8e22