Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP.
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 approximately 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.
Department of Medicine, Columbia University, New York, NY 10032, USA.
Edward
E
Thorp
Gang
G
Li
Tracie A
TA
Seimon
George
G
Kuriakose
David
D
Ron
Ira
I
Tabas
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D001835:Body Weight; D004721:Endoplasmic Reticulum / Q000378:metabolism; D026502:LDL-Receptor Related Proteins; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D051742:Transcription Factor CHOP / Q000172:deficiency* / Q000235:genetics
D001057:Apolipoproteins E; C497250:Ddit3 protein, mouse; D026502:LDL-Receptor Related Proteins; D008074:Lipoproteins; C116415:Lrp4 protein, mouse; D011973:Receptors, LDL; D051742:Transcription Factor CHOP