Soluble beta-amyloid peptides mediate vasoactivity via activation of a pro-inflammatory pathway.
Freshly solubilized beta-amyloid (Abeta) peptides display vasoactive properties, increasing both the magnitude and the duration of endothelin-1-induced vasoconstriction. We show that Abeta vasoactivity is mediated by the stimulation of a pro-inflammatory pathway involving activation of secretory phospholipase A(2) (PLA(2)), mitogen activated protein kinase (MAPK) kinase (MEK1/2), p38 MAPK, cytosolic PLA(2), and the release of arachidonic acid. Ultimately, arachidonic acid is metabolized into proinflammatory eicosanoids via the 5-lipoxygenase and cyclooxygenase-2 (COX-2) enzymes, both of which we show to be required for A beta vasoactivity. Accordingly, p38 MAPK activity is higher in the brains of transgenic mice that overproduce A beta, and COX-2 immunoreactivity is increased in the cerebrovasculature of these transgenic animals. Taken together, our data show that freshly solubilized A beta peptides can trigger a pro-inflammatory reaction in the vasculature that can be blocked by inhibiting specific target molecules, providing the basis for novel therapeutic intervention.
Paris
D
D
The Roskamp Institute, University of South Florida, 3515 E. Fletcher Ave., 33613, Tampa, FL, USA. dparis@com1.med.usf.edu
Town
T
T
Mori
T
T
Parker
T A
TA
Humphrey
J
J
Mullan
M
M
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D016718:Arachidonic Acid / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D051546:Cyclooxygenase 2; D015777:Eicosanoids / Q000096:biosynthesis; D019332:Endothelin-1 / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007249:Inflammation / Q000473:pathology*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D010455:Peptides / Q000494:pharmacology*; D010741:Phospholipases A / Q000378:metabolism; D010750:Phosphoproteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D002148:Calmodulin-Binding Proteins; D015777:Eicosanoids; D019332:Endothelin-1; D007527:Isoenzymes; D010455:Peptides; D010750:Phosphoproteins; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C094726:p37 calmodulin-binding protein, Bos taurus; D017346:Protein Serine-Threonine Kinases; D010741:Phospholipases A