Published online before print October 6, 2005, doi: 10.1161/01.ATV.0000189159.96900.d9
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Peroxynitrite Causes Endoplasmic Reticulum Stress and Apoptosis in Human Vascular Endothelium
Implications in Atherogenesis
árka LhotákFrom the Henderson Research Centre and McMaster University, Hamilton, Canada.
Correspondence to Richard C. Austin, PhD, Henderson Research Centre, 711 Concession St, Hamilton, Ontario L8V 1C3. E-mail raustin{at}thrombosis.hhscr.org
Objective— Peroxynitrite, a potent oxidant generated by the reaction of NO with superoxide, has been implicated in the promotion of atherosclerosis. We designed this study to determine whether peroxynitrite induces its proatherogenic effects through induction of endoplasmic reticulum (ER) stress.
Methods and Results— Human vascular endothelial cells treated with Sin-1, a peroxynitrite generator, induced the expression of the ER chaperones GRP78 and GRP94 and increased eIF2
phosphorylation. These effects were inhibited by the peroxynitrite scavenger uric acid. Sin-1 caused the depletion of ER–Ca2+, an effect known to induce ER stress, resulting in the elevation of cytosolic Ca2+ and programmed cell death (PCD). Sin-1 treatment was also found, via 3-nitrotyrosine and GRP78 colocalization, to act directly on the ER. Adenoviral-mediated overexpression of GRP78 in endothelial cells prevented Sin-1–induced PCD. Consistent with these in vitro findings, 3-nitrotyrosine was observed and colocalized with GRP78 in endothelial cells of early atherosclerotic lesions from apolipoprotein E–deficient mice.
Conclusions— Peroxynitrite is an ER stress-inducing agent. Its effects include the depletion of ER–Ca2+, a known mechanism of ER stress induction. The observation that 3-nitrotyrosine–containing proteins colocalize with markers of ER stress within early atherosclerotic lesions suggests that peroxynitrite contributes to atherogenesis through a mechanism involving ER stress.
Peroxynitrite induces ER stress in human vascular endothelial cells, depletes ER–Ca2+, and induces programmed cell death. Overexpression of GRP78 prevents peroxynitrite-induced apoptosis. Consistent with these findings, 3-nitrotyrosine and GRP78 overexpression colocalize in early atherosclerotic lesions from apoE–/– mice.
Key Words: endothelium • nitric oxide • endoplasmic reticulum • atherosclerosis • calcium
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