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

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http://hdl.handle.net/10138/344248

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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 , vol. 298 , no. 3 , 101721 . https://doi.org/10.1016/j.jbc.2022.101721

Title: Inactivation of mouse transmembrane prolyl 4-hydroxylase increases blood brain barrier permeability and ischemia-induced cerebral neuroinflammation
Author: Byts, Nadiya; Sharma, Subodh; Malm, Tarja; Kaakinen, Mika; Korhonen, Paula; Jaakkonen, Laura; Keuters, Meike; Huuskonen, Mikko; Pietilä, Ilkka; Koistinaho, Jari; Koivunen, Peppi; Myllyharju, Johanna
Contributor organization: Neuroscience Center
Helsinki Institute of Life Science HiLIFE
Date: 2022-03
Language: eng
Number of pages: 21
Belongs to series: Journal of Biological Chemistry
ISSN: 0021-9258
DOI: https://doi.org/10.1016/j.jbc.2022.101721
URI: http://hdl.handle.net/10138/344248
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 trans membrane 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 inflam-matory 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.
Subject: ARTERY OCCLUSION
AGED MICE
HYPOXIA
STROKE
MECHANISMS
TRANSIENT
3112 Neurosciences
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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