Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke

Ischemic stroke is a leading cause of death and disability, and the mechanisms involved in the neurovascular deterioration after stroke are multifactorial and highly complicated. Hyperglycemia is one of the factors that worsen the neurovascular injury, and it is considered an independent predictor of poor clinical outcomes after stroke. Almost 50% of patients with acute ischemic stroke were present with hyperglycemia at time of admission to the hospital, and half of these patients develop acute hyperglycemia as a stress response without a history of diabetes mellitus. It was found that these patients with acute hyperglycemia have the least favorable clinical outcomes when compared with normoglycemic or even diabetic patients. A large body of evidence from experimental and preclinical studies supports that hyperglycemia exacerbates the neurovascular injury and worsens functional outcome after stroke through increasing the infarct size, hemorrhagic transformation (HT), and disruption of the blood–brain barrier. Previously, we have shown that even mild to moderate hyperglycemia exacerbated the vascular injury and functional outcomes without increasing the infarct size. However, the underlying mechanisms contributing to increased vascular injury and HT in hyperglycemic stroke are not fully understood. Matrix metalloprotease 3 (MMP3) belongs to a big family of zinc endopeptidases that can target and degrade a large number of extracellular matrix and tight junction proteins in the neurovascular unit and promote neurodegeneration. Although MMP3 has been shown to contribute to tissue-type plasminogen activator (tPA)–induced HT, its role in mediating the neurovascular injury in hyperglycemic stroke remains unclear. Thus, in this study we tested the hypothesis that hyperglycemia worsens stroke outcomes through elevated MMP3 activity and that MMP3 inhibition reduces HT and improves functional outcome in hyperglycemic stroke. Background and Purpose—Acute hyperglycemia worsens the clinical outcomes and exacerbates cerebral hemorrhage after stroke. The mediators of hemorrhagic transformation (HT) in hyperglycemic stroke are not fully understood. Matrix metalloproteinase 3 (MMP3) plays a critical role in the tissue-type plasminogen activator–induced HT. However, the role of MMP3 in exacerbating the HT and worsening the functional outcomes in hyperglycemic stroke remains unknown. Methods—Control/normoglycemic and hyperglycemic (blood glucose, 140–200 mg/dL) male Wistar rats were subjected to middle cerebral artery occlusion for 90 minutes and either 24 hours or 7 days reperfusion. MMP3 was inhibited pharmacologically (UK 356618, 15 mg/kg IV at reperfusion) or knocked down in the brain by shRNA lentiviral particles (injected intracerebroventricular). Neurovascular injury was assessed at 24 hours, and functional outcomes were assessed at 24 hours, day 3, and day 7. MMP3 activity was measured in brain homogenate and cerebral macrovessels. Localization of MMP3 within the neurovascular unit after hyperglycemic stroke was demonstrated by immunohistochemistry. Results—Hyperglycemia significantly increased MMP3 activity in the brain after stroke, and this was associated with exacerbated HT and worsened functional outcomes. MMP3 inhibition significantly reduced HT and improved functional outcomes. Conclusions—MMP3 plays a critical role in mediating cerebrovascular injury in hyperglycemic stroke. Our findings point out MMP3 as a potential therapeutic target in hyperglycemic stroke. (Stroke. 2016;47:843-851. DOI: 10.1161/ STROKEAHA.115.011258.)