Anti-monocyte chemoattractant protein-1 gene therapy protects against focal brain ischemia in hypertensive rats.
Monocyte chemoattractant protein-1 (MCP-1) is expressed in the ischemic cortex after focal brain ischemia and appears to exacerbate ischemic damage. The authors examined the effect of gene transfer of dominant negative MCP-1, called 7ND, 90 minutes after induction of focal brain ischemia in hypertensive rats. Adenoviral vectors encoding mutant MCP-1 (Ad7ND; n = 11), or Escherichia coli beta-galactosidase (AdlacZ; n = 17) as control were injected into the lateral ventricle of male spontaneously hypertensive rats. Both AdlacZ (n = 12) and Ad7ND (n = 6) administration provided transgene expression as early as 6 hours after injection and the expression further increased on day 1, followed by a sustained detection on day 5. Five days after ischemia, infarct volume (75 +/- 13 mm, n = 5, mean +/- SD) significantly reduced to 72% of control (104 +/- 22 mm3, n = 5, P < 0.05) by 7ND gene transfer. Numbers of leukocytes in the vessels (48.3 +/- 32.9/cm2) and macrophage/monocyte infiltration (475.2 +/- 125.5/mm2) of the infarct area in the Ad7ND group were significantly less than those measured in the AdlacZ group (143.8 +/- 72.1/cm2 and 671.8 +/- 125.5/mm2, P < 0.05, respectively). In summary, the postischemic gene transfer of dominant negative MCP-1 attenuated the infarct volume and infiltration of inflammatory cells, suggesting potential usefulness of the anti-MCP-1 gene therapy.
Kumai
Yasuhiro
Y
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ooboshi
Hiroaki
H
Takada
Junichi
J
Kamouchi
Masahiro
M
Kitazono
Takanari
T
Egashira
Kensuke
K
Ibayashi
Setsuro
S
Iida
Mitsuo
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D002560:Cerebrovascular Circulation; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy; D006973:Hypertension / Q000503:physiopathology; D007150:Immunohistochemistry; D007962:Leukocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051381:Rats; D019076:Transgenes / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D018932:Chemokine CCL2; D001616:beta-Galactosidase