title: Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke.
abstract: OBJECTIVE
  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.
authors.affiliation: From the Charlie Norwood VA Medical Center (S.H., S.C.F., A.E.), Departments of Physiology (S.H., M.A., S.E.-S., A.E.), Biostatistics (M.H.J.), and Neurology (S.C.F.), Medical College of Georgia, Augusta University; and Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta (S.H., S.C.F., A.E.).
authors.forename: Sherif
authors.initials: S
authors.lastname: Hafez
authors.affiliation: From the Charlie Norwood VA Medical Center (S.H., S.C.F., A.E.), Departments of Physiology (S.H., M.A., S.E.-S., A.E.), Biostatistics (M.H.J.), and Neurology (S.C.F.), Medical College of Georgia, Augusta University; and Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta (S.H., S.C.F., A.E.).
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abdelsaid
authors.affiliation: From the Charlie Norwood VA Medical Center (S.H., S.C.F., A.E.), Departments of Physiology (S.H., M.A., S.E.-S., A.E.), Biostatistics (M.H.J.), and Neurology (S.C.F.), Medical College of Georgia, Augusta University; and Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta (S.H., S.C.F., A.E.).
authors.forename: Sally
authors.initials: S
authors.lastname: El-Shafey
authors.affiliation: From the Charlie Norwood VA Medical Center (S.H., S.C.F., A.E.), Departments of Physiology (S.H., M.A., S.E.-S., A.E.), Biostatistics (M.H.J.), and Neurology (S.C.F.), Medical College of Georgia, Augusta University; and Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta (S.H., S.C.F., A.E.).
authors.forename: Maribeth H
authors.initials: MH
authors.lastname: Johnson
authors.affiliation: From the Charlie Norwood VA Medical Center (S.H., S.C.F., A.E.), Departments of Physiology (S.H., M.A., S.E.-S., A.E.), Biostatistics (M.H.J.), and Neurology (S.C.F.), Medical College of Georgia, Augusta University; and Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta (S.H., S.C.F., A.E.).
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
authors.affiliation: From the Charlie Norwood VA Medical Center (S.H., S.C.F., A.E.), Departments of Physiology (S.H., M.A., S.E.-S., A.E.), Biostatistics (M.H.J.), and Neurology (S.C.F.), Medical College of Georgia, Augusta University; and Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta (S.H., S.C.F., A.E.). aergul@gru.edu.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000201:enzymology* / Q000473:pathology; D055785:Gene Knockdown Techniques / Q000379:methods; D006943:Hyperglycemia / Q000201:enzymology* / Q000473:pathology; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000201:enzymology* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D019278:Matrix Metalloproteinase 3
keywords: blood glucose; brain ischemia; hyperglycemia; intracranial hemorrhages; stroke
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