Matrix Metalloproteinase-12 Induces Blood-Brain Barrier Damage After Focal Cerebral Ischemia

Bharath Chelluboina, From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).
Jeffrey D. Klopfenstein, From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).
David M. Pinson, From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).
David Z. Wang, From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).Follow
Raghu Vemuganti, From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.).
Krishna Kumar Veeravalli, From the Departments of Cancer Biology and Pharmacology (B.C., K.K.V.), Neurosurgery (J.D.K.), Pathology (D.M.P.), and Neurology (D.Z.W.), University of Illinois College of Medicine at Peoria; Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison (R.V.); and Comprehensive Stroke Center, Illinois Neurological Institute, Peoria (J.D.K., D.Z.W.). krishnav@uic.edu.

Document Type

Article

Abstract

BACKGROUND AND PURPOSE: Matrix metalloproteinases (MMPs) have a central role in compromising the integrity of the blood-brain barrier (BBB). The role of MMP-12 in brain damage after ischemic stroke remains unknown. The main objective of the current study is to investigate the effect of MMP-12 suppression at an early time point before reperfusion on the BBB damage in rats. METHODS: Sprague-Dawley rats were subjected to middle cerebral artery occlusion and reperfusion. MMP-12 shRNA-expressing plasmids formulated as nanoparticles were administered at a dose of 1 mg/kg body weight. The involvement of MMP-12 on BBB damage was assessed by performing various techniques, including Evans blue dye extravasation, 2,3,5-triphenyltetrazolium chloride staining, immunoblot, gelatin zymography, and immunofluorescence analysis. RESULTS: MMP-12 is upregulated ≈31-, 47-, and 66-fold in rats subjected 1-, 2-, or 4-hour ischemia, respectively, followed by 1-day reperfusion. MMP-12 suppression protected the BBB integrity by inhibiting the degradation of tight-junction proteins. Either intravenous or intra-arterial delivery of MMP-12 shRNA-expressing plasmid significantly reduced the percent Evans blue dye extravasation and infarct size. Furthermore, MMP-12 suppression reduced the endogenous levels of other proteases, such as tissue-type plasminogen activator and MMP-9, which are also known to be the key players involved in BBB damage. CONCLUSIONS: These results demonstrate the adverse role of MMP-12 in acute brain damage that occurs after ischemic stroke and, thereby, suggesting that MMP-12 suppression could be a promising therapeutic target for cerebral ischemia.

Medical Subject Headings

Animals; Blood-Brain Barrier (enzymology, pathology); Brain (enzymology, pathology); Brain Ischemia (enzymology, pathology); Matrix Metalloproteinase 12 (biosynthesis); Rats; Rats, Sprague-Dawley

Publication Date

12-1-2015

Publication Title

Stroke

E-ISSN

1524-4628

Volume

46

Issue

12

First Page

3523

Last Page

31

PubMed ID

26534974

Digital Object Identifier (DOI)

10.1161/STROKEAHA.115.011031

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