Format

Send to

Choose Destination
J Cereb Blood Flow Metab. 2009 Dec;29(12):1946-54. doi: 10.1038/jcbfm.2009.174. Epub 2009 Aug 12.

Microglial low-density lipoprotein receptor-related protein 1 mediates the effect of tissue-type plasminogen activator on matrix metalloproteinase-9 activity in the ischemic brain.

Author information

1
Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Abstract

Studies in animal models of cerebral ischemia indicate that besides its thrombolytic effect, treatment with tissue-type plasminogen activator (tPA) also induces an increase in matrix metalloproteinase-9 (MMP-9) activity in the ischemic tissue associated with the development of cerebral edema. Earlier, we had shown that the low-density lipoprotein receptor-related protein 1 (LRP1) is a substrate for tPA in the brain. In this study, we investigated the effect of the interaction between tPA and microglial LRP1 on MMP-9 activity after middle cerebral artery occlusion (MCAO). We found that exposure to oxygen-glucose deprivation (OGD) conditions increases MMP-9 activity in wild-type (Wt) and plasminogen-deficient (Plg(-/-)) microglia, but not in tPA (tPA(-/-)) or LRP1-deficient (macLRP-) cells. Treatment with tPA increases MMP-9 expression in tPA(-/-) but not in macLRP- microglia. Middle cerebral artery occlusion increases MMP-9 expression and activity in Wt but not in tPA(-/-) or macLRP- mice, and treatment with tPA increases MMP-9 activity in tPA(-/-) mice but not in macLRP- animals. Finally, MCAO-induced ischemic edema and degradation of the interendothelial right junction protein claudin-5 were significantly attenuated in tPA(-/-) and macLRP- mice. The results of our study indicate that the interaction between tPA and microglial LRP1 increases MMP-9 expression and activity resulting in the degradation of claudin-5 and development of cerebral edema.

PMID:
19672275
DOI:
10.1038/jcbfm.2009.174
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center