University of Oulu

Byts, N., Sharma, S., Malm, T., Kaakinen, M., Korhonen, P., Jaakkonen, L., Keuters, M., Huuskonen, M., Pietilä, I., Koistinaho, J., Koivunen, P., & Myllyharju, J. (2022). Inactivation of mouse transmembrane prolyl 4-hydroxylase increases blood brain barrier permeability and ischemia-induced cerebral neuroinflammation. Journal of Biological Chemistry, 298(3), 101721. https://doi.org/10.1016/j.jbc.2022.101721

Inactivation of mouse transmembrane prolyl 4-hydroxylase increases blood brain barrier permeability and ischemia-induced cerebral neuroinflammation

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Author: Byts, Nadiya1; Sharma, Subodh1; Malm, Tarja2;
Organizations: 1Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
2A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
3Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 6.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022050633445
Language: English
Published: American Society for Biochemistry and Molecular Biology, 2022
Publish Date: 2022-08-04
Description:

Abstract

Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs) regulate the hypoxic induction of <300 genes required for survival and adaptation under oxygen deprivation. Inhibition of HIF-P4H-2 has been shown to be protective in focal cerebral ischemia rodent models, while that of HIF-P4H-1 has no effects and inactivation of HIF-P4H-3 has adverse effects. A transmembrane prolyl 4-hydroxylase (P4H-TM) is highly expressed in the brain and contributes to the regulation of HIF, but the outcome of its inhibition on stroke is yet unknown. To study this, we subjected WT and P4htm−/− mice to permanent middle cerebral artery occlusion (pMCAO). Lack of P4H-TM had no effect on lesion size following pMCAO, but increased inflammatory microgliosis and neutrophil infiltration was observed in the P4htm−/− cortex. Furthermore, both the permeability of blood brain barrier and ultrastructure of cerebral tight junctions were compromised in P4htm−/− mice. At the molecular level, P4H-TM deficiency led to increased expression of proinflammatory genes and robust activation of protein kinases in the cortex, while expression of tight junction proteins and the neuroprotective growth factors erythropoietin and vascular endothelial growth factor was reduced. Our data provide the first evidence that P4H-TM inactivation has no protective effect on infarct size and increases inflammatory microgliosis and neutrophil infiltration in the cortex at early stage after pMCAO. When considering HIF-P4H inhibitors as potential therapeutics in stroke, the current data support that isoenzyme-selective inhibitors that do not target P4H-TM or HIF-P4H-3 would be preferred.

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Series: Journal of biological chemistry
ISSN: 0021-9258
ISSN-E: 1083-351X
ISSN-L: 0021-9258
Volume: 298
Issue: 3
Article number: 101721
DOI: 10.1016/j.jbc.2022.101721
OADOI: https://oadoi.org/10.1016/j.jbc.2022.101721
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
Funding: This study was supported by the Academy of Finland through Grants 133075 (T. M.), 218129 (P. K.), 278343 (J. K.), 296498 (J. M.) and Academy of Finland Center of Excellence 2012 to 2017 Grant 251314 (J. M.), the S. Jusélius Foundation (P. K. and J. M.), the Jane and Aatos Erkko Foundation (P. K. and J. M.), FibroGen, Inc (J. M.), and the European Union Seventh Framework Program FP7 Grant 607962 (nEUROinflammation) (J. K.).
Academy of Finland Grant Number: 296498
251314
Detailed Information: 296498 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
Dataset Reference: Microarray data files have been deposited to the Gene Expression Omnibus data repository (https://www.ncbi.nlm.nih.gov/geo/, accession number GSE107127). All remaining data are contained within the article.
  https://www.ncbi.nlm.nih.gov/geo/
Copyright information: © 2022 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
  https://creativecommons.org/licenses/by/4.0/