Minoxidil exerts different inhibitory effects on gene expression of lysyl hydroxylase 1, 2, and 3: implications for collagen cross-linking and treatment of fibrosis
| Autor: | Jeroen de Groot, Anne-Marie Zuurmond, Ruud A. Bank, Ernst A. van Dura, Annemarie J. van der Slot-Verhoeven |
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| Přispěvatelé: | Orale Celbiologie (OUD, ACTA), TNO Kwaliteit van Leven |
| Rok vydání: | 2005 |
| Předmět: |
Biomedical Research
Lysyl hydroxylase Lysine Dose time effect relation Concentration response Hydroxylation Gene Expression Regulation Enzymologic Extracellular matrix chemistry.chemical_compound Pyridinoline cross-links Drug activity medicine Humans Protein cross linking Molecular Biology Biology Cells Cultured Chromatography High Pressure Liquid Pyridinoline biology Skin fibrosis Procollagen-Lysine 2-Oxoglutarate 5-Dioxygenase Messenger RNA Fibrosis Drug inhibition Procollagen lysine 2 oxoglutarate 5 dioxygenase Enzyme substrate Hydroxylysine Fibroblast culture chemistry Biochemistry Human cell Minoxidil biology.protein Protein structure Enzyme specificity Collagen Controlled study 2-Aminoadipic Acid medicine.drug Triple helix Drug sensitivity |
| Zdroj: | Matrix Biology, 24, 261-270. Elsevier Matrix Biology, 4, 24, 261-270 Zuurmond, A M, van der Slot-Verhoeven, A J, van Dura, E A, de Groot, J & Bank, R A 2005, ' Minoxidil exerts different inhibitory effects on gene expression of lysyl hydroxylase 1, 2, and 3: implications for collagen cross-linking and treatment of fibrosis ', Matrix Biology, vol. 24, pp. 261-270 . https://doi.org/10.1016/j.matbio.2005.04.002 |
| ISSN: | 0945-053X |
| DOI: | 10.1016/j.matbio.2005.04.002 |
| Popis: | Collagen deposits in fibrotic lesions often display elevated levels of hydroxyallysine (pyridinoline) cross-links. The relation between the occurrence of pyridinoline cross-links and the irreversibility of fibrosis suggests that these cross-links contribute to the aberrant accumulation of collagen. Based on its inhibitory effect on lysyl hydroxylase activity minoxidil has been postulated to possess anti-fibrotic properties by limiting the hydroxylysine supply for hydroxyallysine cross-linking. However, to interfere with hydroxyallysine cross-linking specifically lysyl hydroxylation of the collagen telopeptide should be inhibited, a reaction predominantly catalysed by lysyl hydroxylase (LH) 2b. In this study, we demonstrate that minoxidil treatment of cultured fibroblasts reduces LH1>>LH2b>LH3 mRNA levels dose-and time-dependently, but has essentially no effect on the total number of pyridinoline cross-links in the collagen matrix. Still the collagen produced in the presence of minoxidil displays some remarkable features: hydroxylation of triple helical lysine residues is reduced to 50% and lysylpyridinoline cross-linking is increased at the expense of hydroxylysylpyridinoline cross-linking. These observations can be explained by our finding that LH1 mRNA levels are the most sensitive to minoxidil treatment, corroborating that LH1 has a preference for triple helical lysine residues as substrate. In addition, the non-proportional increase in cross-links (20-fold) with respect to the decrease in lysyl hydroxylation state of the triple helix (2-fold) even suggests that LH1 preferentially hydroxylates triple helical lysine residues at the cross-link positions. We conclude that minoxidil is unlikely to serve as an anti-fibroticum, but confers features to the collagen matrix, which provide insight into the substrate specificity of LH1. © 2005 Elsevier B.V./International Society of Matrix Biology. All rights reserved. Chemicals / CAS: collagen, 9007-34-5; minoxidil, 38304-91-5; procollagen lysine 2 oxoglutarate 5 dioxygenase, 9059-25-0; pyridinoline, 63800-01-1; 2-Aminoadipic Acid, 542-32-5; Collagen, 9007-34-5; hydroxyallysine, 30382-02-6; lysyl hydroxylase 1, human, EC 1.14.11.4; lysyl hydroxylase 3, human, EC 1.14.11.-; Minoxidil, 38304-91-5; PLOD2 protein, human, EC 1.14.11.4; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, EC 1.14.11.4 |
| Databáze: | OpenAIRE |
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