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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 3 Issue 1 Pg. 200-10 (Jan 31 2013) ISSN: 2211-1247 [Electronic] United States
• PMID: 23333278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Apolipoproteins E
• Biomarkers
• Caspase Inhibitors
• Cytokines
• Lipoproteins, LDL
• RNA, Messenger
• Receptors, LDL
• oxidized low density lipoprotein
• Collagen
• Elastin
• Cholesterol
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• Caspase 8

Topics

• Animals
• Apolipoproteins E (deficiency, metabolism)
• Apoptosis (drug effects)
• Atherosclerosis (metabolism, pathology)
• Biomarkers (metabolism)
• Body Weight (drug effects)
• Bone Marrow Cells (drug effects, metabolism, pathology)
• Bone Marrow Transplantation
• Caspase 8 (metabolism)
• Caspase Inhibitors (pharmacology)
• Cell Shape (drug effects)
• Cholesterol (metabolism)
• Collagen (metabolism)
• Cytokines (biosynthesis)
• Elastin (metabolism)
• Female
• Inflammation (pathology)
• Lipoproteins, LDL (pharmacology)
• Macrophages (drug effects, metabolism, pathology, ultrastructure)
• Mice
• Microdissection
• Necrosis
• RNA, Messenger (genetics, metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (deficiency, genetics, metabolism)
• Receptors, LDL (metabolism)
• Up-Regulation (drug effects)