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Caveolin‐1 mediates tissue plasminogen activator‐induced MMP‐9 up‐regulation in cultured brain microvascular endothelial cells
Author(s) -
Jin Xinchun,
Sun Yanyun,
Xu Ji,
Liu Wenlan
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13065
Subject(s) - tissue plasminogen activator , matrix metalloproteinase , plasminogen activator , caveolin 1 , gene knockdown , endothelial stem cell , blood–brain barrier , thrombolysis , chemistry , medicine , endocrinology , apoptosis , biochemistry , central nervous system , in vitro , myocardial infarction
Thrombolysis with tissue plasminogen activator (tPA) increases matrix metalloproteinase‐9 (MMP‐9) activity in the ischemic brain, which exacerbates blood‐brain barrier injury and increases the risk of symptomatic cerebral hemorrhage. The mechanism through which tPA enhances MMP‐9 activity is not well understood. Here we report an important role of caveolin‐1 in mediating tPA‐induced MMP‐9 synthesis. Brain microvascular endothelial cell line bEnd3 cells were incubated with 5 or 20 μg/ml tPA for 24 hrs before analyzing MMP‐9 levels in the conditioned media and cellular extracts by gelatin zymography. tPA at a dose of 20 μg/mL tPA, but not 5 μg/mL, significantly increased MMP‐9 level in cultured media while decreasing it in cellular extracts. Concurrently, tPA treatment induced a 2.3‐fold increase of caveolin‐1 protein levels in endothelial cells. Interestingly, knockdown of Cav‐1 with siRNA inhibited tPA‐induced MMP‐9 mRNA up‐regulation and MMP‐9 increase in the conditioned media, but did not affect MMP‐9 decrease in cellular extracts. These results suggest that caveolin‐1 critically contributes to tPA‐mediated MMP‐9 up‐regulation, but may not facilitate MMP‐9 secretion in endothelial cells.Thrombolysis with tissue plasminogen activator (tPA) increases matrix metalloproteinase‐9 (MMP‐9) activity in the ischemic brain, which exacerbates ischemic blood brain barrier (BBB) injury and increases the risk of symptomatic cerebral hemorrhage. Our results suggest a novel mechanism underlying this tPA‐MMP 9 axis. In response to tPA treatment, caveolin‐1 protein levels increased in endothelial cells, which mediate MMP‐9 mRNA up‐regulation and its secretion into extracellular space. Caveolin‐1 may, however, not facilitate MMP‐9 secretion in endothelial cells. Our data suggest caveolin‐1 as a novel therapeutic target for protecting the BBB against ischemic damage. The schematic outlines tPA‐induced MMP‐9 upreguation.