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Published on: September 28, 2015
Receptor-interacting protein kinase 3 contributes to abdominal aortic aneurysms via smooth muscle cell necrosis and
Qiwei Wang1, Zhenjie Liu1, Jun Ren1
1From the Department of Surgery (Q.W., Z.L., J.R., S.M., C.A., B.L.), Department of Pathology and Laboratory Medicine, School of Medicine and Public Health (Q.W., B.L.), and Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison (Q.W., B.L.); and Department of Vascular Surgery, the Second Affiliated Hospital School of Medicine, Zhejiang University, China (Z.L.).
Rationale:
Depletion of medial smooth muscle cell (SMC) is a major pathological characteristic of abdominal aortic aneurysm (AAA), although the mechanism by which these cells are eliminated remains incompletely understood. We reasoned that necroptosis, a recently described form of necrosis mediated by receptor-interacting protein kinase 3 (RIP3), may contribute to AAA pathology through the induction of SMC death and the significant production of inflammatory cytokines.
Objective:
To test the hypothesis that RIP3-mediated necroptosis is actively involved in aneurysm pathogenesis.
Methods And Results:
RIP3 and RIP1 levels were found to be elevated in human AAAs, most noticeably in SMCs. Elevations of RIP3 and SMC necrosis were also observed in the elastase-induced mouse model of AAAs. Deletion of one or both copies of Rip3 prevented AAA formation. By transplanting Rip3(+/-) aortae to Rip3(+/+) mice, we demonstrated that reduced Rip3 expression in arterial wall was the primary cause of aneurysm resistance. In vitro, adenoviral overexpression of RIP3 was sufficient to trigger SMC necroptosis. Protein kinase C-delta contributed to tumor necrosis factor-α-induced SMC necroptosis by regulating Rip3 expression. Furthermore, Rip3 deficiency impaired tumor necrosis factor-α-induced inflammatory gene expression in aortic SMCs, which was at least in part because of attenuation of p65 Ser536 phosphorylation. In vivo, the lack of RIP3 diminished activation of p65 in SMCs, implicating a necrosis independent function of RIP3 in aneurysms.
Conclusions:
Enhanced RIP3 signaling in aneurysmal tissues contributes to AAA progression by causing SMC necroptosis, as well as stimulating vascular inflammation, and therefore may serve as a novel therapeutic target for AAA treatment.
Insights
Receptor-interacting protein kinase 3 (RIP3)-mediated necroptosis drives abdominal aortic aneurysm (AAA) by causing smooth muscle cell death and inflammation. Inhibiting RIP3 signaling may offer a new therapeutic strategy for AAA.
Area of Science:
- Vascular Biology
- Cell Death Mechanisms
- Immunology
Background:
- Abdominal aortic aneurysm (AAA) is characterized by smooth muscle cell (SMC) depletion.
- The mechanisms of SMC elimination in AAA remain unclear.
- Necroptosis, a form of programmed necrosis mediated by receptor-interacting protein kinase 3 (RIP3), is investigated as a potential contributor to AAA pathogenesis.
Purpose of the Study:
- To investigate the role of RIP3-mediated necroptosis in abdominal aortic aneurysm (AAA) development.
- To determine if RIP3 signaling contributes to SMC death and vascular inflammation in AAA.
Main Methods:
- Quantified RIP3 and RIP1 levels in human AAA tissues and an elastase-induced mouse AAA model.
- Assessed the impact of Rip3 deletion on AAA formation using knockout mice and aortic transplantation.
- Investigated RIP3's role in SMC necroptosis in vitro using adenoviral overexpression and protein kinase C-delta.
- Analyzed the effect of Rip3 deficiency on tumor necrosis factor-α-induced inflammatory gene expression and p65 phosphorylation in SMCs.
Main Results:
- RIP3 and RIP1 levels were elevated in human AAAs, particularly in SMCs.
- RIP3 and SMC necrosis were increased in a mouse AAA model; Rip3 deletion prevented AAA formation.
- RIP3 overexpression induced SMC necroptosis in vitro; RIP3 deficiency reduced TNF-α-induced inflammation and p65 activation in SMCs.
Conclusions:
- Enhanced RIP3 signaling contributes to AAA progression through SMC necroptosis and vascular inflammation.
- RIP3 plays a role in both necrosis-dependent and -independent pathways in AAA pathogenesis.
- RIP3 signaling represents a potential therapeutic target for abdominal aortic aneurysm treatment.
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