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Microsphere embolism‐induced endothelial nitric oxide synthase expression mediates disruption of the blood–brain barrier in rat brain
Author(s) -
Han Feng,
Shirasaki Yasufumi,
Fukunaga Kohji
Publication year - 2006
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/j.1471-4159.2006.04048.x
Subject(s) - enos , blood–brain barrier , nitrotyrosine , nitric oxide synthase , endothelium , vascular permeability , endothelial stem cell , peroxynitrite , chemistry , medicine , nitric oxide , endocrinology , biology , biochemistry , enzyme , central nervous system , superoxide , in vitro
Microsphere embolism (ME)‐induced up‐regulation of endothelial nitric oxide synthase (eNOS) in endothelial cells of brain microvessels was observed 2–48 h after ischemia. eNOS induction preceded disruption of the blood–brain barrier (BBB) observed 6–72 h after ischemia. In vascular endothelial cells, ME‐induced eNOS expression was closely associated with protein tyrosine nitration, which is a marker of generation of peroxynitrite. Leakage of rabbit IgG from microvessels was also evident around protein tyrosine nitration‐immunoreactive microvessels. To determine whether eNOS expression and protein tyrosine nitration in vascular endothelial cells mediates BBB disruption in the ME brain, we tested the effect of a novel calmodulin‐dependent NOS inhibitor, 3‐[2‐[4‐(3‐chloro‐2‐methylphenyl)‐1‐piperazinyl]ethyl]‐5,6‐dimethoxy‐1‐(4‐imidazolylmethyl)‐1H‐indazole dihydrochloride 3.5 hydrate (DY‐9760e), which inhibits eNOS activity and, in turn, protein tyrosine nitration. Concomitant with inhibition of protein tyrosine nitration in vascular endothelial cells, DY‐9760e significantly inhibited BBB disruption as assessed by Evans blue (EB) excretion. DY‐9760e also inhibited cleavage of poly (ADP‐ribose) polymerase as a marker of the apoptotic pathway in vascular endothelial cells. Taken together with previous evidence in which DY‐9760e inhibited brain edema, ME‐induced eNOS expression in vascular endothelial cells likely mediates BBB disruption and, in turn, brain edema.