Objective:
Abdominal aortic aneurysm (AAA) is a common vascular disease with a progressive nature. Currently, no pharmacological treatment is approved to effectively slow aneurysm growth or prevent rupture. We have recently demonstrated that receptor interacting protein kinase 3 (RIP3), a critical mediator of necroptosis, contributes to smooth muscle depletion and vascular inflammation associated with AAA. In this study, we tested the hypothesis that inhibition of necroptosis may mitigate aneurysm progression using Necrostatin-1 (Nec-1) or an optimized form of Nec-1 called Nec-1s (7-Cl-O-Nec-1), known inhibitors of another necroptosis mediator RIP1.
Approach and Results:
Using elastase perfusion model, we first demonstrated that Nec-1 attenuated aneurysm formation when administered daily by intraperitoneal (IP) injection started 30 min before aneurysm induction. Nec-1 also profoundly reduced elastin fragmentation, macrophage infiltration and SMC necrosis after elastase perfusion. To test whether RIP1 inhibitors can inhibit AAA progression, we randomly divided mice to four groups 7 days after elastase perfusion when aortic dilatation is small but significant. Group 1 was sacrificed to obtain a baseline aortic dilatation, while Group 2, 3, and 4 received daily IP injections of DMSO, Nec-1 (3.2 mg/kg/day) or Nec-1s (1.6mg/kg/day), respectively. 14 days after perfusion, mice in Group 2 displayed larger aneurysmal expansion as compared to Group 1 (
P
<0.05), a reflection of aneurysm growth. In contrast, mice in Group 3 and 4 showed similar aortic dilatations compared to mice in Group 1 (
P
>0.05), indicating insignificant aneurysmal growth. Furthermore, real-time PCR and histological analyses demonstrated that RIP1 inhibition significantly reduced aortic accumulation of proinflammatory cytokines and inflammatory cell infiltration.
Conclusions:
Taken together, our study suggests that necroptosis may serve as a therapeutic target for AAAs. Pharmacological inhibition of RIP1 kinase activity prevented aneurysm formation and stabilized pre-existing aneurysms in mice.
Receptor interacting protein kinase 1 (RIPK1) in hepatocytes does not mediate murine acetaminophen toxicity
