Matrix metalloprotease 3 (MMP3) is an endopeptidase with broad substrate specificity that can target and degrade the components of the neurovascular unit. MMP3 was shown to be a critical mediator of the tPA-induced hemorrhagic transformation (HT) after stroke. The role of MMP3 in mediating neurovascular injury in hyperglycemic stroke was not previously reported. Accordingly, this study tested the hypothesis that MMP3 focal knockdown in the brain reduces HT and improves functional outcomes in hyperglycemic stroke.
Methods: MMP3 shRNA lentiviral particles or an empty vector (EV) was injected into both hemispheres to the lateral ventricles of male Wistar rats. Two weeks later, Control and mildly HG rats (140-200 mg/dl, achieved by 30% glucose injection (IP) 15 min prior to surgery, n=7-9/group) were subjected to 90 min middle cerebral artery occlusion and 24 h reperfusion. At 24 h, neurological deficit, infarct size, edema, Hb content in ischemic hemispheres and HT occurrence rate (HT index) were measured. In an additional group of animals, the spatial expression of MMP3 within the neurovascular unit was determined by immunohistochemistry.
Results: MMP3 knockdown significantly reduced HT index, Hb content and edema with no effect on infarct size and this was associated with improved functional outcomes (Table). MMP3 expression was more evident in HG animals and co-localized with the neurons, blood vessels and pericytes but not astrocytes.
Conclusion: MMP3 knockdown reduced the vascular injury and improved the functional outcomes. Our findings point out MMP3 as a potential therapeutic target in hyperglycemic stroke.