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

Research output: Contribution to journalArticle

149 Scopus citations

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 languageEnglish (US)
Pages (from-to)200-210
Number of pages11
JournalCell Reports
Volume3
Issue number1
DOIs
StatePublished - Jan 31 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Lin, J., Li, H., Yang, M., Ren, J., Huang, Z., Han, F., Huang, J., Ma, J., Zhang, D., Zhang, Z., Wu, J., Huang, D., Qiao, M., Jin, G., Wu, Q., Huang, Y., Du, J., & Han, J. (2013). A Role of RIP3-Mediated Macrophage Necrosis in Atherosclerosis Development. Cell Reports, 3(1), 200-210. https://doi.org/10.1016/j.celrep.2012.12.012