FasL shedding is reduced by hypothermia in experimental stroke.
Protection by mild hypothermia has previously been associated with better mitochondrial preservation and suppression of the intrinsic apoptotic pathway. It is also known that the brain may undergo apoptotic death via extrinsic, or receptor-mediated pathways, such as that triggered by Fas/FasL. Male Sprague-Dawley rats subjected to 2 h middle cerebral artery occlusion with 2 h intraischemic mild hypothermia (33 degrees C) were assayed for Fas, FasL and caspase-8 expression. Ischemia increased Fas, but decreased FasL by approximately 50-60% at 6 and 24 h post-insult. Mild hypothermia significantly reduced expression of Fas and processed caspase-8 both by approximately 50%, but prevented ischemia-induced FasL decreases. Fractionation revealed that soluble/shed FasL (sFasL) was decreased by hypothermia, while membrane-bound FasL (mFasL) increased. To more directly assess the significance of the Fas/FasL pathway in ischemic stroke, primary neuron cultures were exposed to oxygen glucose deprivation. Since FasL is cleaved by matrix metalloproteinases (MMPs), and mild hypothermia decreases MMP expression, treatment with a pan-MMP inhibitor also decreased sFasL. Thus, mild hypothermia is associated with reduced Fas expression and caspase-8 activation. Hypothermia prevented total FasL decreases, and most of it remained membrane-bound. These findings reveal new observations regarding the effect of mild hypothermia on the Fas/FasL and MMP systems.
Liu
Liping
L
Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, California, USA.
Kim
Jong Youl
JY
Koike
Maya A
MA
Yoon
Yone Jung
YJ
Tang
Xian Nan
XN
Ma
Hualong
H
Lee
Hokyou
H
Steinberg
Gary K
GK
Lee
Jong Eun
JE
Yenari
Midori A
MA
D000704:Analysis of Variance; D000818:Animals; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D007036:Hypothermia, Induced / Q000379:methods*; D000860:Hypoxia; D007511:Ischemia / Q000628:therapy*; D008297:Male; D020782:Matrix Metalloproteinases / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism
D053222:Fas Ligand Protein; C491898:Fas protein, rat; D019014:fas Receptor; D053181:Caspase 8; D020782:Matrix Metalloproteinases; D005947:Glucose