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Protein kinase C-β distinctly regulates blood-brain barrier-forming capacity of Brain Microvascular endothelial cells and outgrowth endothelial cells

Kadir, Rais Reskiawan A.; Alwjwaj, Mansour; Bayraktutan, Ulvi

Protein kinase C-β distinctly regulates blood-brain barrier-forming capacity of Brain Microvascular endothelial cells and outgrowth endothelial cells Thumbnail


Authors

Rais Reskiawan A. Kadir

Mansour Alwjwaj



Abstract

Outgrowth endothelial cells (OECs) provide an endogenous repair mechanism and thus maintain endothelial barrier integrity. As inhibition of protein kinase C-β (PKC-β) activity has been shown to attenuate endothelial damage in various pathological conditions including hyperglycaemia and ischaemic injury, the present study comparatively assessed the effect of LY333531, a PKC-β inhibitor, on the cerebral barrier integrity formed by OECs or human brain microvascular endothelial cells (HBMECs). To this end, an in vitro model of human BBB established by co-culture of astrocytes and pericytes with either OECs or HBMECs was exposed to 4h of oxygen-glucose deprivation with/out LY333531 (0.05 µM). The inhibition of PKC-β protected the integrity and function of the BBB formed by HBMECs, as evidenced by increases in transendothelial electrical resistance and decreases in sodium fluorescein flux. It also attenuated ischaemia-evoked actin cytoskeleton remodelling, oxidative stress, and apoptosis in HBMECs. In contrast, treatments with LY333531 exacerbated the deleterious effect of ischaemia on the integrity and function of BBB formed by OECs while augmenting the levels of oxidative stress, apoptosis, and cytoskeletal reorganisation in OECs. Interestingly, the magnitude of damage in all aforementioned parameters, notably oxidative stress, was lower with low dose of LY333531 (0.01 µM). It is therefore possible that the therapeutic concentration of LY333531 (0.05 µM) may neutralise the activity of NADPH oxidase and thus trigger a negative feedback mechanism which in turn exacerbate the detrimental effects of ischaemic injury. In conclusion, targeting PKC-β signalling pathway in ischaemic settings requires close attention while using OECs as cellular therapeutic.

Journal Article Type Article
Acceptance Date Jun 17, 2022
Online Publication Date Jun 28, 2022
Publication Date Jun 28, 2022
Deposit Date Jun 29, 2022
Publicly Available Date Jun 29, 2022
Journal Metabolic Brain Disease
Print ISSN 0885-7490
Electronic ISSN 1573-7365
Publisher Springer Science and Business Media LLC
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1007/s11011-022-01041-1
Keywords Cellular and Molecular Neuroscience; Neurology (clinical); Biochemistry
Public URL https://nottingham-repository.worktribe.com/output/8766012
Publisher URL https://link.springer.com/article/10.1007/s11011-022-01041-1

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