ArticlePloS one2014
Upregulated copper transporters in hypoxia-induced pulmonary hypertension.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 65 citations in OpenAlex.
- Emerging Roles of Regulated Cell Death-mediated Inflammation in Pathophysiology of Ocular Diseases.Journal of ophthalmic & vision research · 2026Review
- Cuproptosis-related molecular alterations in a neonatal rat model of hypoxic-ischemic brain damage.Frontiers in neurology · 2026Article
- Disruption of NF-κB-Mediated Copper Homeostasis Sensitizes Breast Cancer to Cuproptosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Copper Homeostasis and Cuproptosis As Potential Intervention Strategy in Atherosclerosis.Journal of cardiovascular translational research · 2025Review
- Key copper homeostasis genes and inflammatory mechanisms in ischemic stroke: A bioinformatics and experimental study.Functional & integrative genomics · 2025Article
- Novel Role of Copper Transporter CTR1 and Therapeutic Potential of Copper Chelators in Retinal Ischemia-Reperfusion Injury.Investigative ophthalmology & visual science · 2025Article
- Advances in novel cell death mechanisms in breast cancer: intersecting perspectives on ferroptosis, cuproptosis, disulfidptosis, and pyroptosis.Molecular cancer · 2025Review
- Interaction of ferroptosis and cuproptosis in the perspective of pulmonary hypertension.Frontiers in cardiovascular medicine · 2025Review
- Altered copper transport in oxidative stress-dependent brain endothelial barrier dysfunction associated with Alzheimer's disease.Vascular pharmacology · 2024Article
- Roles of Copper Transport Systems Members in Breast Cancer.Cancer medicine · 2024Review
- Clays and Wound Healing.Materials (Basel, Switzerland) · 2024Review
- Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.Frontiers in molecular neuroscience · 2024Review
- A hypothesis: Potential contributions of metals to the pathogenesis of pulmonary artery hypertension.Life sciences · 2024Review
- MAD-microbial (origin of) Alzheimer's disease hypothesis: from infection and the antimicrobial response to disruption of key copper-based systems.Frontiers in neuroscience · 2024Review
- Copper in Gynecological Diseases.International journal of molecular sciences · 2023Review
- Molecular regulation and therapeutic implications of cell death in pulmonary hypertension.Cell death discovery · 2023Review
- Roxadustat: Do we know all the answers?Biomolecules & biomedicine · 2023Review
- Potential Roles of Metals in the Pathogenesis of Pulmonary and Systemic Hypertension.International journal of biological sciences · 2023Review
- Metallomics in pulmonary arterial hypertension patients.Pulmonary circulation · 2023Article
- Copper in cancer: from limiting nutrient to therapeutic target.Frontiers in oncology · 2023Review
Corrections and comments
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
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