Reduced Apoptosis and Plaque Necrosis in Advanced Atherosclerotic Lesions of Apoe−/− and Ldlr−/− Mice Lacking CHOP

• Published in: Cell metabolism 2009-05, Vol.9 (5), p.474-481
• Main Authors: Thorp, Edward, Li, Gang, Seimon, Tracie A., Kuriakose, George, Ron, David, Tabas, Ira
• Format: Article
• Language: English
• Subjects: Animals; Aorta - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Apoptosis; Atherosclerosis - metabolism; Atherosclerosis - pathology; Body Weight; Endoplasmic Reticulum - metabolism; HUMDISEASE; Lipoproteins - blood; Mice; Mice, Inbred C57BL; Mice, Knockout; Necrosis; Receptors, LDL - deficiency; Receptors, LDL - genetics; Transcription Factor CHOP - deficiency; Transcription Factor CHOP - genetics
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2009.03.003

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.