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 ∼50% and lesional apoptosis by 35% in the CHOP-deficient mice. Similar results were found in fat-fed Chop−/−;Ldlr−/− 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.
