Macrophage Autophagy Plays a Protective Role in Advanced Atherosclerosis

被引：625

作者：

Liao, Xianghai ^{[1
]}

Sluimer, Judith C. ^{[1
]}

Wang, Ying ^{[1
,2
]}

Subramanian, Manikandan ^{[1
]}

Brown, Kristy ^{[3
]}

Pattison, J. Scott ^{[4
]}

Robbins, Jeffrey ^{[4
]}

Martinez, Jennifer ^{[5
]}

Tabas, Ira ^{[1
,2
,3
]}

机构：

[1] Columbia Univ, Dept Med, New York, NY 10032 USA

[2] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA

[3] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA

[4] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA

[5] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

来源：

CELL METABOLISM | 2012年 / 15卷 / 04期

基金：

美国国家卫生研究院;

关键词：

ENDOPLASMIC-RETICULUM STRESS; APOPTOTIC CELLS; BASAL AUTOPHAGY; FOAM CELLS; DEATH; PHAGOCYTOSIS; ACTIVATION; CLEARANCE;

D O I：

10.1016/j.cmet.2012.01.022

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

In advanced atherosclerosis, macrophage apoptosis coupled with defective phagocytic clearance of the apoptotic cells (efferocytosis) promotes plaque necrosis, which precipitates acute atherothrombotic cardiovascular events. Oxidative and endoplasmic reticulum (ER) stress in macrophages are important causes of advanced lesional macrophage apoptosis. We now show that proapoptotic oxidative/ER stress inducers trigger another stress reaction in macrophages, autophagy. Inhibition of autophagy by silencing ATG5 or other autophagy mediators enhances apoptosis and NADPH oxidase-mediated oxidative stress while at the same time rendering the apoptotic cells less well recognized by efferocytes. Most importantly, macrophage ATG5 deficiency in fat-fed Ldlr(-/-) mice increases apoptosis and oxidative stress in advanced lesional macrophages, promotes plaque necrosis, and worsens lesional efferocytosis. These findings reveal a protective process in oxidatively stressed macrophages relevant to plaque necrosis, suggesting a mechanism-based strategy to therapeutically suppress atherosclerosis progression and its clinical sequelae.

引用

页码：545 / 553

页数：9

共 33 条

[1] EVIDENCE THAT THE DEATH OF MACROPHAGE FOAM CELLS CONTRIBUTES TO THE LIPID CORE OF ATHEROMA [J].