The Endoplasmic Reticulum Stress-C/EBP Homologous Protein Pathway-Mediated Apoptosis in Macrophages Contributes to the Instability of Atherosclerotic Plaques

Abstract

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. Methods and 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 Ϫ/Ϫ mice. The rupture of atherosclerotic plaques was significantly reduced in high cholesterol-fed Chop Ϫ/Ϫ /Apoe Ϫ/Ϫ mice compared with Chop ϩ/ϩ /Apoe Ϫ/Ϫ 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. Key Words: acute coronary syndrome Ⅲ CHOP Ⅲ ER stress Ⅲ Bax Ⅲ apoptosis A cute coronary syndrome, including myocardial infarction and unstable angina, is most frequently caused by an occlusive coronary thrombosis at the site of a preexisting atherosclerotic plaque. [1][2][3][4][5] The formation of coronary thrombosis is generally the result of the rupture of an atherosclerotic plaque, followed by the aggregation of platelets and the formation of fibrin. Therefore, clarification of the mechanisms by which an atherosclerotic plaque becomes vulnerable to rupture would be useful for preventing the onset of acute coronary syndrome. Atherosclerosis is a chronic inflammatory disease of the arterial wall. [1][2][3]6 Macrophages ingest an excess amount of oxidized low-density lipoprotein (LDL) and are converted into foam cells, which then secrete various inflammatory cytokines. Metalloproteinases secreted by macrophages and apoptosis of macrophage-derived foam cells affect the stability of plaques. Thus, monocytes/macrophages play a key role in the instability of atherosclerotic plaques. Conclusion-TheRecently, Myoishi et al 5 reported that the induction of apoptosis and the activation of the endoplasmic reticulum (ER) stress pathway, including the induction of C/EBP homologous protein (CHOP)/growth arrest and DNA damage-inducible gene0153 (GADD153), a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors, were detected in macrophages and smooth muscle cells within ruptured plaques, but not within stable fibrous plaques, in humans. They also reported that the levels of ...

D4F alleviates macrophage-derived foam cell apoptosis by inhibiting CD36 expression and ER stress-CHOP pathway

“…Furthermore, the apoptosis and expression of CHOP were reduced in atherosclerotic lesions of D4F-treated apoE Ϫ / Ϫ mice. The translocation of ATF6 to the nucleus and phosphorylation of PERK play critical roles in the ER stress-CHOP pathway ( 8,31,32 ). Recently, we showed that ATF6 and PERK upregulate CHOP expression and subsequently mediate ox-LDLinduced apoptosis in macrophages ( 10 ).…”

“…* P < 0.05, ** P < 0.01 versus control group; # P < 0.05, ## P < 0.01 versus ox-LDL group; & P < 0.05, && P < 0.01 versus TM group. prolonged ER stress ( 7,8,30 ). CHOP defi ciency reduces macrophage apoptosis and plaque necrosis in advanced atherosclerotic lesions ( 9 ).…”

“…The ER stress-mediated apoptotic pathway is activated when macrophages are exposed to atherogenic factors that trigger ER stress, such as oxidized LDL (ox-LDL), oxidized phospholipids, "free" cholesterol, and hyperglycemia ( 1,6 ). CHOP, a specific pro-apoptotic transcription factor under condition of ER stress, has been confi rmed to mediate macrophage apoptosis and contribute to the instability of atherosclerotic plaques, whereas the defi ciency of CHOP has been demonstrated to protect macrophages from ER stress-mediated apoptosis in vitro and in advanced atherosclerotic plaques of mice (7)(8)(9). Our previous studies have demonstrated that ox-LDL can induce macrophage apoptosis by upregulating CHOP expression during the formation of macrophage-derived foam cells, whereas quercetin protects macrophages from ox-LDL-induced apoptosis by inhibiting CHOP expression ( 10,11 ).…”

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

“…To gain additional insights into the potential regulating mechanisms of ET-1 in diabetes, we have further investigated the role of C/EBP in mediating high glucose-induced upregulation of ET-1 in cultured human EC. Based on the fact that C/EBPa, -b, and -d isoforms play a major role in various aspects of vascular pathophysiology, [30][31][32] the implication of these transcription factors in the regulation of ET-1 was considered in this study.…”

Coding Microsatellite Frameshift Mutations Accumulate in Atherosclerotic Carotid Artery Lesions: Evaluation of 26 Cases and Literature Review

“…The noncoding microsatellite markers (BAT25, BAT26, CAT25) were selected because of their high sensitivity for the detection of MMR deficiency (9,15 (17)(18)(19)(20)(21). These analyses were complemented by a comprehensive literature search on atherosclerotic lesions and MMR deficiency.…”