title: Microparticles generated during chronic cerebral ischemia deliver proapoptotic signals to cultured endothelial cells.
abstract: Circulating microparticles (MPs) are involved in many physiological processes and numbers are increased in a variety of cardiovascular disorders. The present aims were to characterize levels of MPs in a rodent model of chronic cerebral hypoperfusion (CCH) and to determine their signaling properties. MPs were isolated from the plasma of rats exposed to CCH and quantified by flow cytometry. When MPs were added to cultured endothelial cells or normal rat kidney cells they induced cell death in a time and dose dependent manner. Analysis of pellets by electron microscopy indicates that cell death signals are carried by particles in the range of 400 nm in diameter or less. Cell death involved the activation of caspase 3 and was not a consequence of oxidative stress. Inhibition of the Fas/FasL signaling pathway also did not improve cell survival. MPs were found to contain caspase 3 and treating the MPs with a caspase 3 inhibitor significantly reduced cell death. A TNF-α receptor blocker and a TRAIL neutralizing antibody also significantly reduced cell death. Levels of circulating MPs are elevated in a rodent model of chronic cerebral ischemia. MPs with a diameter of 400 nm or less activate the TNF-α and TRAIL signaling pathways and may deliver caspase 3 to cultured cells.
authors: Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors: Sarah C
authors: SC
authors: Schock
authors: University of Ottawa, Neuroscience Graduate Program, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors: Hamidreza
authors: H
authors: Edrissi
authors: Ottawa Hospital Research Institute, Kidney Centre, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors: Dylan
authors: D
authors: Burger
authors: Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors: Robert
authors: R
authors: Cadonic
authors: Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors: Antoine
authors: A
authors: Hakim
authors: Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada. Electronic address: charliet@uottawa.ca.
authors: Charlie
authors: C
authors: Thompson
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002450:Cell Communication; D002470:Cell Survival; D055252:Cell-Derived Microparticles / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002908:Chronic Disease; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010316:Particle Size; D051381:Rats; D020318:Rats, Long-Evans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3
keywords: Apoptosis; Cerebral ischemia; Microparticles; TNF-α; TRAIL