Selective inhibition of brain endothelial Rhokinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin
Web of Science
AuthorNiego, B; Lee, N; Larsson, P; de Silva, TM; Au, AE-L; McCutcheon, F; Medcalf, RL
Source TitlePLoS One
PublisherPUBLIC LIBRARY SCIENCE
University of Melbourne Author/sAu, Amanda
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsNiego, B., Lee, N., Larsson, P., de Silva, T. M., Au, A. E. -L., McCutcheon, F. & Medcalf, R. L. (2017). Selective inhibition of brain endothelial Rhokinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin. PLOS ONE, 12 (5), https://doi.org/10.1371/journal.pone.0177332.
Access StatusOpen Access
Rho-kinase (ROCK) inhibition, broadly utilised in cardiovascular disease, may protect the blood-brain barrier (BBB) during thrombolysis from rt-PA-induced damage. While the use of nonselective ROCK inhibitors like fasudil together with rt-PA may be hindered by possible hypotensive side-effects and inadequate capacity to block detrimental rt-PA activity in brain endothelial cells (BECs), selective ROCK-2 inhibition may overcome these limitations. Here, we examined ROCK-2 expression in major brain cells and compared the ability of fasudil and KD025, a selective ROCK-2 inhibitor, to attenuate rt-PA-induced BBB impairment in an in vitro human model. ROCK-2 was highly expressed relative to ROCK-1 in all human and mouse brain cell types and particularly enriched in rodent brain endothelial cells and astrocytes compared to neurons. KD025 was more potent than fasudil in attenuation of rt-PA- and plasminogen-induced BBB permeation under normoxia, but especially under stroke-like conditions. Importantly, only KD025, but not fasudil, was able to block rt-PA-dependent permeability increases, morphology changes and tight junction degradation in isolated BECs. Selective ROCK-2 inhibition further diminished rt-PA-triggered myosin phosphorylation, shape alterations and matrix metalloprotease activation in astrocytes. These findings highlight ROCK-2 as the key isoform driving BBB impairment and brain endothelial damage by rt-PA and the potential of KD025 to optimally protect the BBB during thrombolysis.
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