MMP-2/9-cleaved occludin promotes endothelia cell death in ischemic stroke

Although recanalization via thrombolysis and/or thrombectomy has proven to be a beneficial treatment for ischemic stroke, their application are severely limited due to increased risk of symptomatic intracerebral hemorrhage (ICH) as a result of ongoing blood brain barrier (BBB) damage. Degradation of tight junction protein is a key feature of BBB disruption, while endothelial cell death is a major factor in compromising BBB and subsequent ICH. We recently reported that ischemia-induced cleavage of occludin led to the production of two major occludin fragments, which were detectable in the blood circulation of ischemic stroke rats. Here, we show that one of the occludin fragment (55-kDa) was generated by the cleavage of matrix metalloproteinase (MMP)-2/9. Moreover, the treatment of endothelial cells with the MMP-cleaved occludin fragment dramatically increased cell death compared with treatment with whole occludin protein, suggesting this 55-kDa occludin fragment as a key factor in inducing endothelial cell death. Our findings demonstrate that MMP-2/9 cleaved occludin fragment may contribute to BBB damage following ischemic stroke through promoting endothelial cell death.