JCB logo
Imagine Science Film Festival
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online 3 October 2005. doi:10.1083/jcb.200502078
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 1, 61-73
This Article
Right arrow Full Text
Right arrow PDF (Full Text)
Right arrow PPT slides of all figures
Right arrow Supplemental Material Index
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by DeVries-Seimon, T.
Right arrow Articles by Tabas, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by DeVries-Seimon, T.
Right arrow Articles by Tabas, I.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*UniGene
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CHOLESTEROL
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Article

 Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor

Tracie DeVries-Seimon1, Yankun Li1, Pin Mei Yao1, Elizabeth Stone1, Yibin Wang3, Roger J. Davis4, Richard Flavell5, and Ira Tabas1,2

1 Department of Medicine, Columbia University, New York, NY 10032
2 Departments of Anatomy & Cell Biology and Physiology & Cellular Biophysics, Columbia University, New York, NY 10032
3 Departments of Anesthesiology and Medicine, University of California at Los Angeles, Los Angeles, CA 90095
4 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
5 Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520

Correspondence to Ira Tabas: iat1{at}columbia.edu

Macrophage death in advanced atherosclerosis promotes necrosis and plaque destabilization. A likely cause of macrophage death is accumulation of free cholesterol (FC) in the ER, leading to activation of the unfolded protein response (UPR) and C/EBP homologous protein (CHOP)–induced apoptosis. Here we show that p38 MAPK signaling is necessary for CHOP induction and apoptosis. Additionally, two other signaling pathways must cooperate with p38-CHOP to effect apoptosis. One involves the type A scavenger receptor (SRA). As evidence, FC loading by non-SRA mechanisms activates p38 and CHOP, but not apoptosis unless the SRA is engaged. The other pathway involves c-Jun NH2-terminal kinase (JNK)2, which is activated by cholesterol trafficking to the ER, but is independent of CHOP. Thus, FC-induced apoptosis requires cholesterol trafficking to the ER, which triggers p38-CHOP and JNK2, and engagement of the SRA. These findings have important implications for understanding how the UPR, MAPKs, and the SRA might conspire to cause macrophage death, lesional necrosis, and plaque destabilization in advanced atherosclerotic lesions.

Abbreviations used in this paper: ACAT, acyl-coenzyme A-cholesterol acyltransferase; ac-LDL, acetylated low density lipoprotein; AGE, advanced glycation end-product; CD, cyclodextrin; CHOP, C/EBP homologous protein; CML-BSA, carboxymethyllysine modified BSA; DiI, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; FC, free cholesterol; JNK, c-Jun NH2-terminal kinase; LDL, low density lipoprotein; MK2, mitogen-activated protein kinase–activated protein kinase 2; MKK3, MAP kinase kinase 3; PERK, ds-RNA–activated protein kinase-like ER kinase; SRA, scavenger receptor type A; UPR, unfolded protein response; VLDL, very low density lipoprotein.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents