Journal
CELL METABOLISM
Volume 9, Issue 5, Pages 474-481Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2009.03.003
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Funding
- NIH [HL75662, HL57560, DK47119, ES08681]
- American Heart Association
- Heritage Affiliate
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Endoplasmic reticulum (ER) stress is a hallmark of advanced atherosclerosis, but its causative role in plaque progression is unknown. In vitro studies have implicated the ER stress effector CHOP in macrophage apoptosis, a process involved in plaque necrosis in advanced atheromata. To test the effect of CHOP deficiency in vivo, aortic root lesions of fat-fed Chop+/+;Apoe-/- and Chop-/-;Apoe-/-mice were analyzed for size and morphology. Despite similar plasma lipoproteins, lesion area was 35% smaller in Chop-/-;Apoe-/- mice. Most importantly, plaque necrosis was reduced by similar to 50% and lesional apoptosis by 35% in the CHOP-deficient mice. Similar results were found in fat-fed Chop-/-; Ldir-/- versus Chop+/+;Ldlr-/- mice. Thus, CHOP promotes plaque growth, apoptosis, and plaque necrosis in fat-fed Apoe-/- and Ldlr-/- mice. These data provide direct evidence for a causal link between the ER stress effector CHOP and plaque necrosis and suggest that interventions weakening this arm of the UPR may lessen plaque progression.
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