Copper stimulates proliferation of human endothelial cells under culture

Hu, Guo‐fu

doi:10.1002/(sici)1097-4644(19980601)69:3<326::aid-jcb10>3.0.co;2-a

Cited by 378 publications

(258 citation statements)

References 32 publications

(44 reference statements)

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“…Prior studies also showed that much lower doses (0.5 mM) of Cu 2þ ions do not influence SMC proliferation, although endothelial cells proliferated rapidly. 48 Here, we show that CuSO 4 in the range of 0.01 M induces SMC proliferation, results that suggest that the effect of Cu 2þ ions on cells is specific to cell type and dose. At the higher doses of CuSO 4 (0.1 M), although no cell death was observed, cells appeared rounded in the first 3 days after CuSO 4 addition but gradually assumed a more spread morphology.…”

Section: Discussionmentioning

confidence: 53%

Biomimetic Regeneration of Elastin Matrices Using Hyaluronan and Copper Ion Cues

Kothapalli

Ramamurthi

2009

Tissue Engineering Part A

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Current efforts to tissue engineer elastin-rich vascular constructs and grafts are limited because of the poor elastogenesis of adult vascular smooth muscle cells (SMCs) and the unavailability of appropriate cues to upregulate and enhance cross-linking of elastin precursors (tropoelastin) into organized, mature elastin fibers. We earlier showed that hyaluronan (HA) fragments greatly enhance tropo-and matrix-elastin synthesis by SMCs, although the yield of matrix elastin is low. To improve matrix yields, here we investigate the benefits of adding copper (Cu 2+ ) ions (0.01 M and 0.1 M), concurrent with HA (756-2000 kDa), to enhance lysyl oxidase (LOX)-mediated elastin cross-linking machinery. Although absolute elastin amounts in test groups were not different from those in controls, on a per-cell basis, 0.1 M of Cu 2+ ions slowed cell proliferation (5.6 AE 2.3-fold increase over 21 days vs 22.9 AE 4.2-fold for non-additive controls), stimulated synthesis of collagen (4.1 AE 0.4-fold), tropoelastin (4.1 AE 0.05-fold) and cross-linked matrix elastin (4.2 ± 0.7-fold). LOX protein synthesis increased 2.5 times in the presence of 0.1 M of Cu 2+ ions, and these trends were maintained even in the presence of HA fragments, although LOX functional activity remained unchanged in all cases. The abundance of elastin and LOX in cell layers cultured with 0.1 M of Cu 2+ ions and HA fragments was qualitatively confirmed using immunoflourescence. Scanning electron microscopy images showed that SMC cultures supplemented with 0.1 M of Cu 2+ ions and HA oligomers and large fragments exhibited better deposition of mature elastic fibers (*1 mm diameter). However, 0.01 M of Cu 2+ ions did not have any beneficial effect on elastin regeneration. In conclusion, the results suggest that supplying 0.1 M of Cu 2+ ions to SMCs to concurrently (a) enhance per-cell yield of elastin matrix while allowing cells to remain viable and synthetic and not density-arrested in long-term culture because of their moderating effects on otherwise rapid cell proliferation and (b) provide additional benefits of enhanced elastin fiber formation and cross-linking within these tissue-engineered constructs.

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Section: Discussionmentioning

confidence: 53%

Biomimetic Regeneration of Elastin Matrices Using Hyaluronan and Copper Ion Cues

Kothapalli

Ramamurthi

2009

Tissue Engineering Part A

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“…Iron and copper are required by proliferating cancer cells during carcinogenesis [32,39,59,77] and high levels of iron and copper were found in certain tumour cells and tissues, including breast cancer cells [17,33]. As iron and copper metabolism is up-regulated in neoplastic tumours [29,39,41,44,47,59,62,65,72], 56MESS and other complexes in this class should be assessed, in combination with cisplatin, in the cancer models that have elevated iron and copper metabolism.…”

Section: Discussionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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“…This is the level of DRI for Cu (0.9 mg/day) plus Cu supplementation (2 mg/day) for humans. It should note that many studies in cultured cells use high levels of Cu, ranging from 100 to 500 μM CuCl 2 or CuSO 4 [19][20][21].…”

Section: Discussionmentioning

confidence: 99%

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Zhou

Jiang

Kang

2008

Journal of Molecular and Cellular Cardiology

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Previous studies have shown that dietary copper supplementation reversed heart hypertrophy induced by pressure overload in a mouse model. The present study was undertaken to understand the cellular basis of copper-induced regression of cardiac hypertrophy. Primary cultures of neonatal rat cardiomyocytes were treated with phenylephrine at a final concentration of 100 μM in cultures for 48 h to induce cellular hypertrophy. The hypertrophied cardiomyocytes were exposed to copper sulfate at a final concentration of 5 μM in cultures for additional 24 h. This copper treatment reduced the size of the hypertrophied cardiomyocytes, as measured by flow cytometry, protein content in cells, cell volume and cardiomyocyte hypertrophy markers including beta myosin heavy chain protein, skeletal alpha-actin, and atrial natriuretic peptide. Cell cycle analysis and cell sorting of p-histone-3 labeled cardiomyocytes indicated that cell division was not involved in the copper-induced regression of cardiomyocyte hypertrophy. Copper also inhibited PE-induced apoptosis, determined by a TUNEL assay. Because copper stimulates vascular endothelial growth factor (VEGF) production through activation of hypoxia-inducible transcription factor, an anti-VEGF antibody at a final concentration of 2 ng/ml in cultures was used and shown to blunt copper-induced regression of cell hypertrophy. Conversely, VEGF alone at a final concentration of 0.2 μg/ml reversed cell hypertrophy as the same as copper did. This study demonstrates that both copper and VEGF reduce the size of hypertrophied cardiomyocytes, and copper regression of cardiac hypertrophy is VEGF dependent.

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Copper stimulates proliferation of human endothelial cells under culture

Cited by 378 publications

References 32 publications

Biomimetic Regeneration of Elastin Matrices Using Hyaluronan and Copper Ion Cues

Biomimetic Regeneration of Elastin Matrices Using Hyaluronan and Copper Ion Cues

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

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