title: Role of necroptosis in autophagy signaling during hepatic ischemia and reperfusion.
abstract: Ischemia and reperfusion (I/R) is a complex phenomenon involving massive inflammation and cell death. Necroptosis refers to a newly described cell death as "programmed necrosis" that is controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, which is involved in the pathogenesis of several inflammatory diseases. Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli and involves crosstalk between different modes of cell death and inflammation. In this study, we investigated pattern changes in necroptosis and its role in autophagy signaling during hepatic I/R. Male C57BL/6 mice were subjected to 60min of ischemia followed by 3h reperfusion. Necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.65mg/kg) was administered intraperitoneally 5min before reperfusion. Hepatic I/R significantly increased the level of RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome formation, which were attenuated by Nec-1. I/R also significantly increased serum levels of alanine aminotransferase, tumor necrosis factor-α, and interleukin-6, which were attenuated by Nec-1. Meanwhile, hepatic I/R activated autophagy and mitophagy, as evidenced by increased LC3-II, PINK1, and Parkin, and decreased sequestosome 1/p62 protein expression. Nec-1 attenuated these changes and attenuated the increased levels of autophagy-related protein (ATG) 3, ATG7, Rab7, and cathepsin B protein expression during hepatic I/R. Moreover, hepatic I/R activated the extracellular signal-regulated kinase (ERK) pathway, and Nec-1 attenuated this increase. Taken together, our findings suggest that necroptosis contributes to hepatic damage during I/R, which induces autophagy via ERK activation.
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors: Jeong-Min
authors: JM
authors: Hong
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors: Seok-Joo
authors: SJ
authors: Kim
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea. Electronic address: sunmee@skku.edu.
authors: Sun-Mee
authors: SM
authors: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy; D008099:Liver / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury; D015398:Signal Transduction
keywords: Autophagy; Ischemia/reperfusion; Liver; Necroptosis; Necrostatin-1