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Abstract
Constitutive genetic deletion of the adaptor protein p66(Shc) was shown to protect from ischaemia/reperfusion injury. Here, we aimed at understanding the molecular mechanisms underlying this effect in stroke and studied p66(Shc) gene regulation in human ischaemic stroke. Ischaemia/reperfusion brain injury was induced by performing a transient middle cerebral artery occlusion surgery on wild-type mice. After the ischaemic episode and upon reperfusion, small interfering RNA targeting p66(Shc) was injected intravenously. We observed that post-ischaemic p66(Shc) knockdown preserved blood-brain barrier integrity that resulted in improved stroke outcome, as identified by smaller lesion volumes, decreased neurological deficits, and increased survival. Experiments on primary human brain microvascular endothelial cells demonstrated that silencing of the adaptor protein p66(Shc) preserves claudin-5 protein levels during hypoxia/reoxygenation by reducing nicotinamide adenine dinucleotide phosphate oxidase activity and reactive oxygen species production. Further, we found that in peripheral blood monocytes of acute ischaemic stroke patients p66(Shc) gene expression is transiently increased and that this increase correlates with short-term neurological outcome. Post-ischaemic silencing of p66(Shc) upon reperfusion improves stroke outcome in mice while the expression of p66(Shc) gene correlates with short-term outcome in patients with ischaemic stroke.
Highlights
Stroke is associated with major disabilities and mortality.[1]
Cerebral microvascular endothelial cells are a main component of the blood–brain barrier (BBB)[7] which divides the cerebral circulation from brain tissue
To study the effect of post-ischaemic p66Shc silencing on stroke, a transient MCAO surgery was performed on wt mice to induce I/R brain injury
Summary
Ischaemic stroke is amenable to thrombolysis in patients presenting early after symptom onset,[5] vascular leakage and the ensuing oedema formation during reperfusion contributes importantly to neurological deficits.[6] Cerebral microvascular endothelial cells are a main component of the blood–brain barrier (BBB)[7] which divides the cerebral circulation from brain tissue These cells are interconnected by tight and adherens junction proteins[7] whose integrity is critical for stroke outcome.[8] disruption of the BBB following ischaemia/reperfusion (I/R) leads to vascular leakage and infiltration of plasma components into the brain tissue leading to oedema and further organ damage.[9,10,11] Overproduction of reactive oxygen species (ROS) following I/R is considered a key mechanism leading to BBB damage.[12] p66Shc, an isoform of the mammalian adaptor protein Shc,[13,14] is a crucial mediator of ROS production in several disease states[15,16,17,18] thereby leading to cellular apoptosis.[19,20,21] much of the vasculoprotective properties observed by genetic deletion of p66Shc in mice are the result of reduced oxidative stress and in turn preserved endothelial function.[15,16,17]
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