Abstract 14198: Peptide-siRNA Nanoparticles Targeting NF-kB Subunit P50 Suppress Experimental Abdominal Aortic Aneurysm Progression and Prevent Rupture

Abstract

Rationale: Abdominal aortic aneurysm (AAA) is a progressive vascular condition associated with high risk of mortality due to rupture if left untreated. AAA is an inflammatory process with excessive local production of extracellular matrix degrading enzymes, leading to dilatation, and rupture of the abdominal aorta. We posit that targeting NF-κB, a signaling pathway that controls inflammation, will halt AAA progression and prevent rupture. Methods and Results: In an elastase-induced AAA model we observe that NF-κB activation increases progressively post-elastase perfusion. Unexpectedly, we found that AAA progression is marked by predominant nuclear localization of the NF-κB p50 subunit at the exclusion of p65. Using the amphipathic peptide p5RHH to form nanocomplexes with siRNA, we show that NF-κB p50, but not p65 knockdown mitigates small AAA progression. Since elastase-induced AAA is self-limiting, we turn to an AAA model by topical application of elastase combined with TGF-β inhibition, which leads to rapid aortic diameter expansion and rupture in 50% of experimental animals. Systemic delivery of p5RHH-siRNA nanoparticles suppressing p50 protect 100% of male mice from rupture (and sudden death) in this model but does not significantly mitigate aneurysm expansion. In both models, knockdown of p50 is accompanied by significant decrease in inflammatory infiltrate, release of various cytokines, inducible nitric oxide synthase expression, and cell apoptosis. Conclusions: These results identify NF-κB pathway p50 subunit as a critical key modulator of the inflammatory process in AAA and p50 represents a potential therapeutic target in the medical management of AAA to prevents expansion and rupture. Figure 1. (A) Elastase + anti-TGF-β AAA model. (B) Aortic rupture with hematoma (arrow). (C) Survival curve (n = 6-10 mice per treatment group). p50 knockdown prevents rupture and death (C) but not AAA expansion (D). * P < 0.05, ** P < 0.01, *** P < 0.001. inact.=inactive.