The endoplasmic reticulum stress-C/EBP homologous protein pathway-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques.
OBJECTIVE
To elucidate whether and how the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway in macrophages is involved in the rupture of atherosclerotic plaques.


RESULTS
Increases in macrophage-derived foam cell death in coronary atherosclerotic plaques cause the plaque to become vulnerable, thus resulting in acute coronary syndrome. The ER stress-CHOP/growth arrest and DNA damage-inducible gene-153 (GADD153) pathway is induced in the macrophage-derived cells in atherosclerotic lesions and is involved in plaque formation. However, the role of CHOP in the final stage of atherosclerosis has not been fully elucidated. Many CHOP-expressing macrophages showed apoptosis in advanced ruptured atherosclerotic lesions in wild-type mice, whereas few apoptotic cells were observed in Chop(-/-) mice. The rupture of atherosclerotic plaques was significantly reduced in high cholesterol-fed Chop(-/-)/Apoe(-/-) mice compared with Chop(+/+)/Apoe(-/-) mice. Furthermore, using mice that underwent bone marrow transplantation, we showed that expression of CHOP in macrophages significantly contributes to the formation of ruptures. By using primary cultured macrophages, we further showed that unesterified free cholesterol derived from incorporated denatured low-density lipoprotein was accumulated in the ER and induced ER stress-mediated apoptosis in a CHOP-Bcl2-associated X protein (Bax) pathway-dependent manner.


CONCLUSIONS
The ER stress-CHOP-Bax-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques.
Tsukano
Hiroto
H
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Gotoh
Tomomi
T
Endo
Motoyoshi
M
Miyata
Keishi
K
Tazume
Hirokazu
H
Kadomatsu
Tsuyoshi
T
Yano
Masato
M
Iwawaki
Takao
T
Kohno
Kenji
K
Araki
Kimi
K
Mizuta
Hiroshi
H
Oike
Yuichi
Y
D054058:Acute Coronary Syndrome / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000473:pathology* / Q000503:physiopathology*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005487:Foam Cells / Q000473:pathology / Q000502:physiology; D015870:Gene Expression; D066298:In Vitro Techniques; D008264:Macrophages / Q000473:pathology* / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000502:physiology
D001057:Apolipoproteins E; C494827:Bax protein, mouse; C497250:Ddit3 protein, mouse; D051028:bcl-2-Associated X Protein; D051742:Transcription Factor CHOP; D002784:Cholesterol