PMID- 26839355 OWN - NLM STAT- MEDLINE DCOM- 20160718 LR - 20220410 IS - 1524-4628 (Electronic) IS - 0039-2499 (Print) IS - 0039-2499 (Linking) VI - 47 IP - 3 DP - 2016 Mar TI - Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke. PG - 843-51 LID - 10.1161/STROKEAHA.115.011258 [doi] AB - 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. CI - (c) 2016 American Heart Association, Inc. FAU - Hafez, Sherif AU - Hafez S AD - 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.). FAU - Abdelsaid, Mohammed AU - Abdelsaid M AD - 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.). FAU - El-Shafey, Sally AU - El-Shafey S AD - 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.). FAU - Johnson, Maribeth H AU - Johnson MH AD - 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.). FAU - Fagan, Susan C AU - Fagan SC AD - 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.). FAU - Ergul, Adviye AU - Ergul A AD - 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. LA - eng GR - VA999999/Intramural VA/United States GR - R01 NS063965/NS/NINDS NIH HHS/United States GR - I01 BX000891/BX/BLRD VA/United States GR - NS063965/NS/NINDS NIH HHS/United States GR - R01 NS083559/NS/NINDS NIH HHS/United States GR - R01NS083559/NS/NINDS NIH HHS/United States GR - I01 BX000347/BX/BLRD VA/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160202 PL - United States TA - Stroke JT - Stroke JID - 0235266 RN - 0 (Matrix Metalloproteinase Inhibitors) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM CIN - Stroke. 2016 Jun;47(6):e172. PMID: 27217514 CIN - Stroke. 2016 Jun;47(6):e173. PMID: 27217515 MH - Animals MH - Cerebral Hemorrhage/*enzymology/pathology MH - Gene Knockdown Techniques/methods MH - Hyperglycemia/*enzymology/pathology MH - Male MH - Matrix Metalloproteinase 3/*biosynthesis MH - Matrix Metalloproteinase Inhibitors/pharmacology MH - Rats MH - Rats, Wistar MH - Recovery of Function/drug effects/*physiology MH - Stroke/*enzymology/pathology MH - Treatment Outcome PMC - PMC4766051 MID - NIHMS750335 OTO - NOTNLM OT - blood glucose OT - brain ischemia OT - hyperglycemia OT - intracranial hemorrhages OT - stroke EDAT- 2016/02/04 06:00 MHDA- 2016/07/19 06:00 PMCR- 2017/03/01 CRDT- 2016/02/04 06:00 PHST- 2015/08/21 00:00 [received] PHST- 2015/12/27 00:00 [accepted] PHST- 2017/03/01 00:00 [pmc-release] PHST- 2016/02/04 06:00 [entrez] PHST- 2016/02/04 06:00 [pubmed] PHST- 2016/07/19 06:00 [medline] AID - STROKEAHA.115.011258 [pii] AID - 10.1161/STROKEAHA.115.011258 [doi] PST - ppublish SO - Stroke. 2016 Mar;47(3):843-51. doi: 10.1161/STROKEAHA.115.011258. Epub 2016 Feb 2.