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.
Thorp
Edward
E
Department of Medicine, Columbia University, New York, NY 10032, USA.
Li
Gang
G
Seimon
Tracie A
TA
Kuriakose
George
G
Ron
David
D
Tabas
Ira
I
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