TY - JOUR
T1 - Phospholipase A2 superfamily members play divergent roles after spinal cord injury
AU - López-Vales, Rubèn
AU - Ghasemlou, Nader
AU - Redensek, Adriana
AU - Kerr, Bradley J.
AU - Barbayianni, Efrosini
AU - Antonopoulou, Georgia
AU - Baskakis, Constantinos
AU - Rathore, Khizr I.
AU - Constantinou-Kokotou, Violetta
AU - Stephens, Daren
AU - Shimizu, Takao
AU - Dennis, Edward A.
AU - Kokotos, George
AU - David, Samuel
PY - 2011/1/1
Y1 - 2011/1/1
N2 - Spinal cord injury (SCI) results in permanent loss of motor functions. A significant aspect of the tissue damage and functional loss may be preventable as it occurs, secondary to the trauma. We show that the phospholipase A 2 (PLA2) superfamily plays important roles in SCI. PLA2 enzymes hydrolyze membrane glycerophospholipids to yield a free fatty acid and lysophospholipid. Some free fatty acids (arachidonic acid) give rise to eicosanoids that promote inflammation, while some lysophospholipids (lysophosphatidylcholine) cause demyelination. We show in a mouse model of SCI that two cytosolic forms [calcium-dependent PLA2 group IVA (cPLA 2 GIVA) and calcium-independent PLA2 group VIA (iPLA 2 GVIA)], and a secreted form [secreted PLA2group IIA (sPLA2 GIIA)] are up-regulated. Using selective inhibitors and null mice, we show that these PLA2s play differing roles. cPLA2 GIVA mediates protection, whereas sPLA2 GIIA and, to a lesser extent, iPLA2 GVIA are detrimental. Furthermore, completely blocking all three PLA2s worsens outcome, while the most beneficial effects are seen by partial inhibition of all three. The partial inhibitor enhances expression of cPLA2 and mediates its beneficial effects via the prostaglandin EP1 receptor. These findings indicate that drugs that inhibit detrimental forms of PLA2 (sPLA2 and iPLA2) and upregulate the protective form (cPLA2) may be useful for the treatment of SCI.
AB - Spinal cord injury (SCI) results in permanent loss of motor functions. A significant aspect of the tissue damage and functional loss may be preventable as it occurs, secondary to the trauma. We show that the phospholipase A 2 (PLA2) superfamily plays important roles in SCI. PLA2 enzymes hydrolyze membrane glycerophospholipids to yield a free fatty acid and lysophospholipid. Some free fatty acids (arachidonic acid) give rise to eicosanoids that promote inflammation, while some lysophospholipids (lysophosphatidylcholine) cause demyelination. We show in a mouse model of SCI that two cytosolic forms [calcium-dependent PLA2 group IVA (cPLA 2 GIVA) and calcium-independent PLA2 group VIA (iPLA 2 GVIA)], and a secreted form [secreted PLA2group IIA (sPLA2 GIIA)] are up-regulated. Using selective inhibitors and null mice, we show that these PLA2s play differing roles. cPLA2 GIVA mediates protection, whereas sPLA2 GIIA and, to a lesser extent, iPLA2 GVIA are detrimental. Furthermore, completely blocking all three PLA2s worsens outcome, while the most beneficial effects are seen by partial inhibition of all three. The partial inhibitor enhances expression of cPLA2 and mediates its beneficial effects via the prostaglandin EP1 receptor. These findings indicate that drugs that inhibit detrimental forms of PLA2 (sPLA2 and iPLA2) and upregulate the protective form (cPLA2) may be useful for the treatment of SCI.
KW - CNS injury
KW - Lipid metabolism
KW - Prostaglandin receptors
KW - Secondary damage
UR - http://www.scopus.com/inward/record.url?scp=82655171632&partnerID=8YFLogxK
U2 - 10.1096/fj.11-183186
DO - 10.1096/fj.11-183186
M3 - Article
C2 - 21868473
SN - 0892-6638
VL - 25
SP - 4240
EP - 4252
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -