A Role of RIP3-Mediated Macrophage Necrosis in Atherosclerosis Development

Juan Lin; Hanjie Li; Min Yang; Junming Ren; Zhe Huang; Felicia Han; Jian Huang; Jianhui Ma; Duanwu Zhang; Zhirong Zhang; Jianfeng Wu; Deli Huang; Muzhen Qiao; Guanghui Jin; Qiao Wu; Yinghui Huang; Jie Du; Jiahuai Han

doi:10.1016/j.celrep.2012.12.012

A Role of RIP3-Mediated Macrophage Necrosis in Atherosclerosis Development

Juan Lin, Hanjie Li, Min Yang, Junming Ren, Zhe Huang, Felicia Han, Jian Huang, Jianhui Ma, Duanwu Zhang, Zhirong Zhang, Jianfeng Wu, Deli Huang, Muzhen Qiao, Guanghui Jin, Qiao Wu, Yinghui Huang, Jie Du, Jiahuai Han

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Abstract

Necrotic death of macrophages has long been known to be present in atherosclerotic lesions but has not been studied. We examined the role of receptor interacting protein (RIP) 3, a mediator of necrotic cell death, in atherosclerosis and found that RIP3^-/-;Ldlr^-/- mice were no different from RIP3^+/+;Ldlr^-/- mice in early atherosclerosis but had significant reduction in advanced atherosclerotic lesions. Similar results were observed in Apoe^-/- background mice. Bone marrow transplantation revealed that loss of RIP3 expression from bone-marrow-derived cells is responsible for the reduced disease progression. While no difference was found in apoptosis between RIP3^-/-;Ldlr^-/- and RIP3^+/+;Ldlr^-/- mice, electron microscopy revealed a significant reduction of macrophage primary necrosis in the advanced lesions of RIP3^-/- mice. In vitro cellular studies showed that . RIP3 deletion had no effect on oxidized low-density lipoprotein (LDL)-induced macrophage apoptosis, but prevented macrophage primary necrosis occurring in response to oxidized LDL under caspase inhibition or RIP3 overexpression conditions. RIP3-dependent necrosis is not postapoptotic, and the increased primary necrosis in advanced atherosclerotic lesions most likely resulted from the increase of RIP3 expression. Our data demonstrate that primary necrosis of macrophages is proatherogenic during advanced atherosclerosis development.

Original language	English (US)
Pages (from-to)	200-210
Number of pages	11
Journal	Cell Reports
Volume	3
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2012.12.012
State	Published - Jan 31 2013

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2012.12.012

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@article{313d431634624712bf2ecdbc7a54db02,

title = "A Role of RIP3-Mediated Macrophage Necrosis in Atherosclerosis Development",

abstract = "Necrotic death of macrophages has long been known to be present in atherosclerotic lesions but has not been studied. We examined the role of receptor interacting protein (RIP) 3, a mediator of necrotic cell death, in atherosclerosis and found that RIP3-/-;Ldlr-/- mice were no different from RIP3+/+;Ldlr-/- mice in early atherosclerosis but had significant reduction in advanced atherosclerotic lesions. Similar results were observed in Apoe-/- background mice. Bone marrow transplantation revealed that loss of RIP3 expression from bone-marrow-derived cells is responsible for the reduced disease progression. While no difference was found in apoptosis between RIP3-/-;Ldlr-/- and RIP3+/+;Ldlr-/- mice, electron microscopy revealed a significant reduction of macrophage primary necrosis in the advanced lesions of RIP3-/- mice. In vitro cellular studies showed that . RIP3 deletion had no effect on oxidized low-density lipoprotein (LDL)-induced macrophage apoptosis, but prevented macrophage primary necrosis occurring in response to oxidized LDL under caspase inhibition or RIP3 overexpression conditions. RIP3-dependent necrosis is not postapoptotic, and the increased primary necrosis in advanced atherosclerotic lesions most likely resulted from the increase of RIP3 expression. Our data demonstrate that primary necrosis of macrophages is proatherogenic during advanced atherosclerosis development.",

author = "Juan Lin and Hanjie Li and Min Yang and Junming Ren and Zhe Huang and Felicia Han and Jian Huang and Jianhui Ma and Duanwu Zhang and Zhirong Zhang and Jianfeng Wu and Deli Huang and Muzhen Qiao and Guanghui Jin and Qiao Wu and Yinghui Huang and Jie Du and Jiahuai Han",

note = "Funding Information: We thank Ping Chen at the School of Life Sciences, Xiamen University for her help with electron microscopy analysis. We thank K. Newton and V.M. Dixit for RIP3 −/− mice. This work was supported by 973 Program 2009CB522200, Natural Science Foundation of China grants 30830092, 30921005, 91029304, 81061160512, 863 program 2012AA02A201, and 111 project B12001. ",

year = "2013",

month = jan,

day = "31",

doi = "10.1016/j.celrep.2012.12.012",

language = "English (US)",

volume = "3",

pages = "200--210",

journal = "Cell Reports",

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TY - JOUR

T1 - A Role of RIP3-Mediated Macrophage Necrosis in Atherosclerosis Development

AU - Lin, Juan

AU - Li, Hanjie

AU - Yang, Min

AU - Ren, Junming

AU - Huang, Zhe

AU - Han, Felicia

AU - Huang, Jian

AU - Ma, Jianhui

AU - Zhang, Duanwu

AU - Zhang, Zhirong

AU - Wu, Jianfeng

AU - Huang, Deli

AU - Qiao, Muzhen

AU - Jin, Guanghui

AU - Wu, Qiao

AU - Huang, Yinghui

AU - Du, Jie

AU - Han, Jiahuai

N1 - Funding Information: We thank Ping Chen at the School of Life Sciences, Xiamen University for her help with electron microscopy analysis. We thank K. Newton and V.M. Dixit for RIP3 −/− mice. This work was supported by 973 Program 2009CB522200, Natural Science Foundation of China grants 30830092, 30921005, 91029304, 81061160512, 863 program 2012AA02A201, and 111 project B12001.

PY - 2013/1/31

Y1 - 2013/1/31

N2 - Necrotic death of macrophages has long been known to be present in atherosclerotic lesions but has not been studied. We examined the role of receptor interacting protein (RIP) 3, a mediator of necrotic cell death, in atherosclerosis and found that RIP3-/-;Ldlr-/- mice were no different from RIP3+/+;Ldlr-/- mice in early atherosclerosis but had significant reduction in advanced atherosclerotic lesions. Similar results were observed in Apoe-/- background mice. Bone marrow transplantation revealed that loss of RIP3 expression from bone-marrow-derived cells is responsible for the reduced disease progression. While no difference was found in apoptosis between RIP3-/-;Ldlr-/- and RIP3+/+;Ldlr-/- mice, electron microscopy revealed a significant reduction of macrophage primary necrosis in the advanced lesions of RIP3-/- mice. In vitro cellular studies showed that . RIP3 deletion had no effect on oxidized low-density lipoprotein (LDL)-induced macrophage apoptosis, but prevented macrophage primary necrosis occurring in response to oxidized LDL under caspase inhibition or RIP3 overexpression conditions. RIP3-dependent necrosis is not postapoptotic, and the increased primary necrosis in advanced atherosclerotic lesions most likely resulted from the increase of RIP3 expression. Our data demonstrate that primary necrosis of macrophages is proatherogenic during advanced atherosclerosis development.

AB - Necrotic death of macrophages has long been known to be present in atherosclerotic lesions but has not been studied. We examined the role of receptor interacting protein (RIP) 3, a mediator of necrotic cell death, in atherosclerosis and found that RIP3-/-;Ldlr-/- mice were no different from RIP3+/+;Ldlr-/- mice in early atherosclerosis but had significant reduction in advanced atherosclerotic lesions. Similar results were observed in Apoe-/- background mice. Bone marrow transplantation revealed that loss of RIP3 expression from bone-marrow-derived cells is responsible for the reduced disease progression. While no difference was found in apoptosis between RIP3-/-;Ldlr-/- and RIP3+/+;Ldlr-/- mice, electron microscopy revealed a significant reduction of macrophage primary necrosis in the advanced lesions of RIP3-/- mice. In vitro cellular studies showed that . RIP3 deletion had no effect on oxidized low-density lipoprotein (LDL)-induced macrophage apoptosis, but prevented macrophage primary necrosis occurring in response to oxidized LDL under caspase inhibition or RIP3 overexpression conditions. RIP3-dependent necrosis is not postapoptotic, and the increased primary necrosis in advanced atherosclerotic lesions most likely resulted from the increase of RIP3 expression. Our data demonstrate that primary necrosis of macrophages is proatherogenic during advanced atherosclerosis development.

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SP - 200

EP - 210

JO - Cell Reports

JF - Cell Reports

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ER -

A Role of RIP3-Mediated Macrophage Necrosis in Atherosclerosis Development

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